Substituted-5-methylidene hydantoins with AT1 receptor antagonist properties

ABSTRACT

Substituted 1-benzylimidazole-5-methylidene hydantoins are disclosed as well as methods of preparing them, pharmaceutical compositions containing them, and method of using them. Intermediates useful in the preparation of the compounds of the invention are also disclosed and synthetic methods for preparing the novel intermediates. The compounds are useful as antagonists of angiotensin II and thus are useful in the control of hypertension, hyperaldosteronism, congestive heart failure, surgically induced vascular smooth muscle proliferation, and glaucoma.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of U.S. Ser. No. 07/811,184, filed Dec.20, 1991 now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel substituted derivatives of1-benzylimidazole-5-methylidene hydantoins which are useful aspharmaceutical agents, to methods for their preparation, topharmaceutical compositions which include the compounds and apharmaceutically acceptable carrier, and to pharmaceutical methods oftreatment as well as the use of these agents as diagnostic tools. Thenovel compounds of the present invention are antagonists of angiotensinII (AII) useful in controlling hypertension, hyperaldosteronism,congestive heart failure, and glaucoma in mammals.

The enzyme renin acts on a blood plasma α₂ -globulin, angiotensinogen,to produce angiotensin I, which is then converted byangiotensin-coverting enzyme to AII. The latter substance is a powerfulvasopressor agent which has been implicated as a causative agent forproducing high blood pressure in various mammals, such as rats, dogs,and humans. The compounds of this invention inhibit the action of AII atits receptors on target cells and thus prevent the increase in bloodpressure produced by this hormone-receptor interaction. By administeringa compound of the instant invention to a species of mammal withhypertension due to AII, the blood pressure is reduced. The compounds ofthe invention are also useful for the treatment of congestive heartfailure, hyperaldosteronism, and glaucoma.

European Patent Application 0253310 discloses angiotensin II receptorblocking imidazoles of the formula ##STR1##

European Patent Application 0291969 discloses tetrazole intermediates toantihypertensive compounds ##STR2##

European Patent Application 401030 discloses substituted imidazo-fused7-member ring heterocycles of Formula I and Ia ##STR3## which are usefulas angiotensin II antagonists.

WO 91/00277 discloses substituted imidazoles useful as angiotensin IIblockers ##STR4##

European Patent Applications 403158 and 403159 disclose angiotensin IIreceptor antagonists of formula ##STR5## in which:

R¹ is phenyl, biphenyl, naphthyl, or adamantylmethyl, which areunsubstituted or substituted by 1 to 3 substituents selected from Cl,Br, F, I, C₁ -C₄ -alkyl, nitro, CO₂ R⁷, tetrazol-5-yl, C₁ -C₄ -alkoxy,hydroxy, SC₁ -C₄ alkyl, SO₂ NHR⁷, SO₃ H, CONR⁷ R⁷, CN, SO₂ C₁ -C₄ alkyl,or C_(n) F_(2n1), wherein n is 1 to 3;

R² is C₂ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₃ -C₆cycloalkyl, or (CH₂)₀₋₃ phenyl unsubstituted or substituted by 1 to 3substituents selected from C₁ -C₄ alkyl, nitro, Cl, Br, F, I, hydroxy,C₁ -C₄ alkoxy, or NR⁷ R⁷ ;

X is a single bond, S, or O:

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR⁷, CONR⁷ R⁷, NO₂,or C_(n) F_(2n1), wherein n is 1 to 3;

R⁴ and R⁵ are independently hydrogen, C₁ -C₅ alkyl, phenyl-Y-,naphthyl-Y-, or biphenyl-Y-, wherein the aryl groups are unsubstitutedor substituted by 1 to 3 substituents selected from Cl, Br, F, I, C₁ -C₄alkoxy, hydroxy, CO₂ R⁷, CN, NO₂, tetrazol-5-yl, SO₃ H, CF₃, CONR⁷ R⁷,SO₂ NHR⁷, C₁ -C₄ -alkyl, or NR⁷ R⁷, or by methylenedioxy, phenoxy, orphenyl, except that R⁴ and R⁵ are not both selected from hydrogen or C₁-C₆ alkyl;

Y is a single bond, O, S, or C₁ -C₆ alkyl which is straight or branchedor optionally substituted by phenyl or benzyl, wherein each of the arylgroups is unsubstituted or substituted by halo, NO₂, CF₃, C₁ -C₄ alkyl,C₁ -C₄ alkoxy, CN, or CO₂ R⁷ ;

R⁶ is --Z--COOR⁶ or --Z--CONR⁷ R⁷ ;

Z is a single bond, vinyl, CH₂ --O--CH₂ --, methylene optionallysubstituted by C₁ -C₄ alkyl, 1 or 2 benzyl groups, thienylmethyl, orfurylmethyl, or --C(O)NHCHR⁹ --, wherein R⁹ is H, C₁ -C₄ alkyl, phenyl,benzyl, thienylmethyl, or furylmethyl;

each R⁷ independently is hydrogen, C₁ -C₄ alkyl, or (CH₂)_(m) phenyl,wherein m is 0 to 4; and

R⁶ is hydrogen, C₁ -C₆ alkyl, or 2-di(C₁ C₄ alkyl)amino-2-oxoethyl; or

R⁵ and R⁶ are both hydrogen, R⁴ is --Z--COOR⁸ and Z is other than asingle bond; or a pharmaceutically acceptable salt thereof.

U.S. Pat. No. 4,355,040 discloses imidazole-5-acetic acid derivatives ofthe formula ##STR6## wherein R¹ is lower alkyl, cycloalkyl or phenylwhich may be substituted with 1 to 3 of halogen, nitro, amino,mono(lower alkyl)amino, di(lower alkyl)amino, lower alkyl, loweralkoxyl, benzyloxyl and/or hydroxyl; X¹, X², and X³ are each hydrogen,halogen, nitro, amino, lower alkyl, lower alkoxyl, benzyloxyl orhydroxyl; Y is halogen and R² is hydrogen or lower alkyl; provided thatX¹ is halogen, lower alkyl, lower alkoxyl, benzyloxyl or hydroxyl whenR¹ is unsubstituted or substituted phenyl only with 1 halogen, di(loweralkyl)amino, lower alkyl or lower alkoxyl, and its salts. The compoundsare disclosed as having antihypertensive activity.

However, the compounds disclosed in the above references do not discloseor suggest the novel combination of structural variations found in thecompounds of the present invention described hereinafter.

SUMMARY OF THE INVENTION

The present invention is a compound of Formula I or Ia ##STR7## or apharmaceutically acceptable salt thereof wherein R₁, R₂, R₃, R₄, R₅, R₆,and R₇ are as defined below.

Preferred compounds of the instant invention are those of Formula I orIa wherein

R₁ is

hydrogen,

methyl,

ethyl,

n-propyl,

i-propyl,

n-butyl,

i-butyl,

sec-butyl,

t-butyl,

n-amyl,

i-amyl,

n-hexyl,

aryl,

CH₂ -aryl,

CH₂ -heteroaryl, or

CH₂ -cycloalkyl wherein aryl, heteroaryl, and cycloalkyl are as definedbelow in the detailed description of the invention;

R₂ is

methyl,

ethyl,

propyl,

i-propyl,

n-butyl,

n-pentyl,

2-propenyl,

2-butenyl,

3-butenyl, or

cyclopropyl,

R₃ is

(CH₂)_(n) CO₂ Y or ##STR8## wherein Y is hydrogen or lower alkyl, n is 0or 1, m is 2 to 5;

R₄ is

hydrogen,

alkyl or branched alkyl of from 1 to 8 carbon atoms,

--(CH₂)_(m) X(CH₂)_(n) H m=1-6, n=0-6, and X=O, N, S;

R₅ is hydrogen;

R₆ is

hydrogen,

chlorine,

fluorine,

methyl,

trifluoromethyl, or

methoxy; and

R₇ is oxygen.

More preferred compounds of the instant invention are those of Formula Ior Ia wherein

R₁ is n-butyl, n-pentyl, n-propyl, benzyl, 2-thienylmethyl,3-thienylmethyl, cyclopropylmethyl, cyclohexylmethyl, cyclopentylmethyl,2-methyl-4-thiazolylmethyl, 2-amino-4-thiazolylmethyl, or4-thiazolylmethyl;

R₂ is butyl and propyl;

R₃ is

(CH₂)_(n) CO₂ Y wherein n is 0, Y is hydrogen or methyl;

R₄ is hydrogen or alkyl of 3 to 6 carbons;

R₅ and R₆ are each hydrogen; and

R₇ is oxygen.

Still more preferred compounds of the instant invention are selectedfrom

(E)-4-[[2-Butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-Butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-Butyl-5-[[2,5-dioxo-3-(3-methylbutyl)-4-imidazolidinylidene]methyl]-1H-imidazole-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-Butyl-5-[[2,5-dioxo-3-(3-methylbutyl)-4-imidazolidinylidene]methyl]-1H-imidazole)1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-Butyl-5-[(2,5-dioxo-3-methyl-4-imidazolidinylidene)methyl]-1H-imidazole-1yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-Butyl-5-[(2,5-dioxo-3-methyl-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-Butyl-5-[(2,5-dioxo-3-(phenylmethyl)-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid and its methyl ester

(Z)-4-[[2-Butyl-5-[(2,5-dioxo-3-(phenylmethyl)-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-Butyl-5-[(2,5-dioxo-3-phenyl-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-Butyl-5-[(2,5-dioxo-3-phenyl-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-Butyl-5-[[2,5-dioxo-3-((2-thienyl)methyl)-4-imidazolidinylidene]-methyl]-1H-imidazole-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-Butyl-5-[[2,5-dioxo-3-((2-thienyl)methyl)-4-imidazolidinylidene]methyl]-1H-imidazole-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-Butyl-5-[[2,5-dioxo-3-(4-hydroxybutyl)-4-imidazolidinylidene]methyl]-1H-imidazole-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-Butyl-5-[[2,5-dioxo-3-(4-hydroxybutyl)-4-imidazolidinylidene]methyl]-1H-imidazole-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-Butyl-5-[(3-butyl-1-methyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-Butyl-5-[(3-butyl-1-methyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[3-[(4-chlorophenyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[3-[(4-chlorophenyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-butyl-3-(cyclohexylmethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-butyl-3-(cyclohexylmethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-pentyl-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-pentyl-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[(1,3-dibutyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[(1,3-dibutyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1yl-]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[2,5-dioxo-1,3-bis(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[2,5-dioxo-1,3-bis(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(3-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(3-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-butyl-3-[(5-methyl-2-thienyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-butyl-3-[(5-methyl-2-thienyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(4-thiazolylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(4-thiazolylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-Butyl-5-[[3-[(2-methyl-4-thiazoly)methyl]-2,5-dioxo-1-(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-Butyl-5-[[3-[(2-methyl-4-thiazoly)methyl]-2,5-dioxo-1-(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-butyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-butyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-butyl-3-[(2-amino-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-butyl-3-[(2-amino-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(2-pyridinylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(2-pyridinylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(1H-tetrazol-5-ylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(1H-tetrazol-5-ylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-butyl-3-(1H-imidazol-5-ylmethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-butyl-3-(1H-imidazol-5-ylmethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-butyl-3-[(5-methyl-3-isoxazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-butyl-3-[(5-methyl-3-isoxazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-hexyl-2,5-dioxo-3-(3-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-hexyl-2,5-dioxo-3-(3-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[1-hexyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[1-hexyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-(cyclopropylmethyl)-2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-(cyclopropylmethyl)-2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-(methoxymethyl)-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-(methoxymethyl)-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-(hydroxymethyl)-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-(hydroxymethyl)-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[1-butyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoic acid and its methyl ester,

(E)-4-[[2-butyl-5-[[1-butyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoic acid and its methyl ester,

(Z)-N-[4-[[2-butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]phenyl]-1,1,1-trifluoromethanesulfonamide,

(E)-N-[4-[[2-butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]phenyl]-1,1,1-trifluoromethanesulfonamide,

(Z)-1-Butyl-5-[[2-butyl-3-[[4-(1H-tetrazol-5-yl)phenyl]methyl]-3H-imidazol-4yl]methylene]-2,4-imidazolidinedione,

(E)-1-Butyl-5-[[2-butyl-3-[[4-(1H-tetrazol-5-yl)phenyl]methyl]-3H-imidazol-4-yl]methylene]-2,4-imidazolidinedione,

(Z)-4-[[2-butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoicacid and its methyl ester,

(E)-4-[[2-butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoicacid and its methyl ester,

(Z)-1-Butyl-5-[[2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]-2,4-imidazolidinedione,

(E)-1-Butyl-5-[[2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]-2,4-imidazolidinedione,

1-Butyl-5-[[2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methyl]-2,4-imidazolidinedione,

(Z)-5-[[2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]1-methyl-2,4-imidazolidinedione,

(E)-5-[[2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]1-methyl-2,4-imidazolidinedione,

(Z)-4'[[2-butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl][1,1'-biphenyl]-2-carboxylicacid and its methyl ester,

(E)-4'-[[2-butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl][1,1'-biphenyl]-2-carboxylicacid and its methyl ester,

(Z)-1-[4-[[2-butyl-5-[[2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]phenyl]cyclopentanecarboxylicacid and its methyl ester,

(E)-1-[4-[[2-butyl-5-[[2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]phenyl]cyclopentanecarboxylicacid and its methyl ester,

(Z)-1-[4-[[2-butyl-5-[[1-butyl-[3-(2-methyl-4-thiazoly)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]phenyl]cyclopentanecarboxylicacid and its methyl ester,

(E)-1-[4-[[2-butyl-5-[[1-butyl-[3-(2-methyl-4-thiazoly)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]phenyl]cyclopentanecarboxylicacid and its methyl ester,

(Z)-4-[[2-Butyl-5-[[2,5-dioxo-1,3-bis(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(E)-4-[[2-Butyl-5-[[2,5-dioxo-1,3-bis(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester,

(Z)-4-[[2-butyl-5-[[3-butyl-1-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester, and

(E)-4-[[2-butyl-5-[[(3-butyl-1-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid and its methyl ester.

Preferred useful intermediates in the invention are ##STR9## wherein

R₁ is

H,

Me,

n-Bu,

CH₂ Ph; or ##STR10## wherein

R₈ is H, Br, or ##STR11## and wherein

R₉ is

H,

Me,

n-Bu,

CH₂ OMe,

n-Pr,

CH₂ ##STR12##

Angiotension II mediates a variety of responses in various tissues,including contraction of vascular smooth muscle, excretions of salt andwater from kidney, release of prolactin from pituitary, stimulation ofaldosterone secretion from adrenal gland, and regulation of cell growthin both cardiac and vascular tissue. As antagonists of angiotension II,the compounds of the instant invention are useful in controllinghypertension, hyperaldosteronism, and congestive heart failure inmammals. Compounds of the instant invention also have utility inprevention of vascular occlusion due to smooth muscle proliferationfollowing vascular surgeries such as angioplasty, coronary bypass,transplantation, and the like. Additionally, antihypertensive agents asa class have been shown to be useful in lowering intraocular pressure.Thus, the other inventions are also useful in treating and/or preventingglaucoma.

The present invention is also a pharmaceutical composition foradministering an effective amount of a compound of Formula I or Ia inunit dosage form in the treatment methods mentioned above.

Finally, the present invention is directed to methods for thepreparation of a compound of Formula I or Ia and syntheticintermediates.

DETAILED DESCRIPTION

This invention is a compound of Formula I or Ia ##STR13## or apharmaceutically acceptable salt thereof wherein:

R₁ is

hydrogen,

straight or branched alkyl or alkenyl from 1 to 8 carbon atoms;

alkyl as above with HO, NO₂, CN, NH₂, CO₂ H, CONH₂, CO₂ CH₃, CO₂ C₂ H₅,or CONH₂ substituents;

(CH₂)_(n) aryl wherein n is an integer from 0 to 3 and aryl is Ph or Phsubstituted with Cl, Br, I, F, CH₃, OCH₃, OH, NO₂, CN, CONH₂, CO₂ H,NH₂, NHCH₃, or N(CH₃)₂ groups, methylenedioxy;

(CH₂)_(n) heteroaryl wherein n is an integer from 0 to 3 and heteroarylis 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrrolyl, 3-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 2-oxazolyl, 2-imidazolyl,4-thiazolyl, 4-oxazolyl, 4-imidazolyl, 5-thiazolyl, 5-oxazolyl,5-tetrazole, 3-isoxazole, 4-isoxazole, or 5-isoxazole;

(CH₂)_(n) heteroaryl as above with Me, Et, Pr, Butyl, Cl, Br, I, F, OMe,OH, NO₂, NH₂, NHMe, NMe₂, CO₂ R, SO₂ NHR, SO₃ H, CONR₂ substituents.

(CH₂)_(n) cycloalkyl wherein n is an integer from 0 to 3 and cycloalkylis a saturated or unsaturated ring of 3 to 7 carbon atoms;

(CH₂)_(m) X(CH₂)_(n) H where X is O, S, N, and m and n are eachindependently integral from 1 to 6 carbon atoms;

R₂ is

(CH₂)_(n) cycloalkyl, wherein n is an integer from 0 to 3, of from 3 to6 carbon atoms;

alkyl of from 1 to 6 carbon atoms, or

alkenyl of from 2 to 6 carbon atoms, OC₁ -C₅ alkyl, and SC₁ -C₅ alkyl;

R₃ is

(CH₂)_(n) CO₂ Y or ##STR14## wherein Y is hydrogen or lower alkyl, n isan integer of from 0 to 8, and m is an integer of from 2 to 7;

CH₂ SO₂ NHCOR,

NHSO₂ NHCOR,

NHCONHSO₂ R,

PO(OR)₂,

CONHSO₂ R,

SO₃ H,

B(OH)₂

--SO₂ NHCOR,

--SO₂ NHCONHR, ##STR15## --NHSO₂ CF₃, ##STR16##

R₄ =R₁

R₅ is hydrogen or alkyl of from 1 to 4 carbon atoms;

R₆ is hydrogen, chlorine, bromine, fluorine, methyl, trifluoromethyl, ormethoxy; and

R₇ is oxygen or sulfur.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms, including hydrated forms, are equivalent to unsolvatedforms and are intended to be encompassed within the scope of the presentinvention.

Both E- and Z-isomers, for example, a compound of Formula I or Ia areincluded.

Certain compounds of the present invention possess 1 or more chiralcenters and each center may exist in the R(D) or S(L) configuration. Thepresent invention includes all enantiomeric and epimeric forms as wellas the appropriate mixtures thereof.

In the compounds of Formula I or Ia, the term "alkyl" means a straightor branched hydrocarbon radical having from 1 to 8 carbon atoms andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like, exceptwhere specifically stated otherwise.

The term "alkenyl" is an alkyl group as above bearing 1 double bond atany position with E- or Z-geometry.

The compounds of Formula I or Ia are capable of further forming bothpharmaceutically acceptable acid addition and/or base salts. All ofthese forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compound ofFormula I or Ia include salts derived from nontoxic inorganic acids suchas hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,phosphorous, and the like , as well as the slats derived from nontoxicorganic acids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Suchsalts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated areslats of amino acids such as arginate and the like and gluconate,galacturonate (see, for example, Berge, S. M., et al, "PharmaceuticalSalts," Journal of Pharmaceutical Science 1977;66:1-19).

The acid addition salts of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free base for purposes of the presentinvention.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium magnesium,calcium, and the like. Examples of suitable amines areN,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, N-methylglucamine, and procaine (see, for example,Berge, S. M., et al, "Pharmaceutical Salts," Journal of PharmaceuticalScience 1977;66:1-19).

The base addition salts of acidic compounds are prepared by contactingthe free acid form with a sufficient amount of the desired base toproduce the salt in the conventional manner. The free acid form may beregenerated by contacting the salt form with an acid and isolating thefree acid in the conventional manner. The free acid forms differ fromtheir respective salt forms somewhat in certain physical properties suchas solubility in polar solvents, but otherwise the salts are equivalentto their respective free acid for purposes of the present invention.

Compounds of Formula I or Ia and intermediates therefor may be preparedaccording to the syntheses outlined in Schemes I-VII below. Althoughthese schemes often indicate exact structures, the methods apply widelyto analogous compounds of Formula I or Ia and intermediates therefor,given appropriate consideration to protection and deprotection ofreactive functional groups by methods standard to the art of organicchemistry. The strategy for preparation of compounds of Formula I or Iainvolves oxidation of a 4-chloro-imidazol5-methanol such as 1 (Scheme I)with manganese dioxide in an inert solvent such as tetraphydrofuran,dioxane, acetone, dichloromethane, and the like. The resulting aldehyde,2, is then alkylated with a benzyl halide in the presence of a weakinorganic base such as Na₂ CO₃, K₂ CO₃, or Cs₂ CO₃ in a polar, aproticsolvent like DMF, DMA, N-methyl pyrrolidone or DMSO. Preferredconditions for the benzylation employ 1 to 5 equivalents of Cs₂ CO₃ inDMF at 0°-35° C. for 1 to 12 hours. Under the preferred conditions, thealkylated product, 3, is formed to a large excess over itsimidazole-N-regiosomer and is easily purified by crystallization orchromatography methods standard to the art of organic chemistry. The4-chloro group is reduced by catalytic hydrogenation to convert 3 to 4.Preferred conditions for this reduction employ 5% to 10% Pd on carbon, apolar protic solvent such as methanol or ethanol, and a weak base suchas NaOAc, KOAc, or LiOAc. Saponification of 4 with strong aqueous basesuch as NaOH, KOH, or LiOH using a water miscible organic cosolvent suchas methanol, ethanol, or tetrahydrofuran gives the intermediateimidazole aldehyde, 5.

Intermediate hydantoins (Scheme II), 7, are prepared in a two-stepprocess, starting from the appropriately N-substituted-glycine ester, 6.Treatment of 6 with a slight excess of dilute aqueous HCl and KNCO givesan intermediate urea that is cyclized to the hydantoin, 7, by treatingthe hot concentrated HCl. Furthermore compounds of the Type 6 may betreated with alkylisocyanates in methylene chloride at room temperature.The intermediate substituted ureas may then be cyclized in warm acid orbase to afford hydantoins of the Type 1 bearing a R₄ substituent.

Condensation of imidazole-aldehyde intermediates 4 or 5 with hydantoinintermediates 7, as described in Scheme III, affords products of FormulaI or Ia such as 10 and 11. The condensation is performed under stronglybasic conditions in water or alcohol-water mixtures at 100°-120° C.Suitable bases include NaOH, KOH, LiOH, (Me)₄ NOH, and the like, with(Me)₄ NOH preferred. Regiosomeric products 10 and 11 are separated bycrystallization or chromatography methods standard to the art of organicchemistry.

An alternative method of condensation to give esters 12 and 13 offersgreater control of regiochemistry about the double bond as shown inScheme IV. Intermediate imidazole-aldehyde, 4, is condensed with thephosphate-hydantoin, 9, which is prepared according to the publishedmethod of Meanwell, et al, J.O.C., 56, 6879-6904 (1991) Depending uponthe conditions used in the condensation, the ratio of Z to E isomerswill vary. With alkozides in alcoholic solvent a 1:1 ratio is observed.With 1,8-diazabicyclo[4.4.0]undec-7-ene (DBU), lithium chloride, andacetaonitrile solvent, the Z isomer is formed in greater quantities thanthe E isomer with a Z:E ratio of ≧4:1. Compounds 12 and 13 are compoundsof Formula I or Ia and may be converted to Compounds 10 and 11, as shownin Scheme III which are also compounds of Formula I or Ia, bysaponification of the ester group.

Furthermore Compounds 12 and 13 may be converted to compoundsrepresented by Compound 16 by treatment with base in a suitable solventand with an electrophile. Preferred conditions include treating Compound12 with 5 equivalents of K₂ CO₃ in DMF and an alkyl iodide.

In situations where the phosphonate 9 cannot be prepared an alternativeprocedure is available as outlined in Scheme V. The phosphonate 9a isprepared by treatment of diethyl 2,5-diozo-4-imidazolidonone phosphonatewith an electrophile and base in a suitable solvent. Preferredconditions include treating 9 with 5 equivalents K₂ CO₃ in DMF and analkyl iodide at room temperature and stirring for 4 to 16 hours. Withless reactive electrophiles 9 can be treated with one equivalent of NaHin THF or DMF and the electrophile added at room temperature.

The phosphonate 9a is condensed with the intermediate aldehyde 4 (SchemeV) to give mixtures of the alkylidinene hydantoins 14 and 15. When DBUis used as a base in methylene chloride the Z isomer is formedpredominantly. Compound 14 can be alkylated by treatment with base and areactive electrophile. Typical condition include treating 14 with 5equivalents of K₂ CO₃, in DMF, and then adding the electrophile.Reactions proceed normally at room temperature. With less reactiveelectrophiles the reaction temperature may be elevated and additionalquantities of electrophile added.

Ester saponification when R₄ and R₁ are not hydrogen is achieved byrefluxing Compound 16 in acid; 2N HCl is preferable. Prolonged heatingwith concentrated HCl causes Z to E isomerisation. Alternatively thet-butyl ester, Compound 17, is hydrolyzed by treatment withtrifluoroacetic acid. Scheme VI represents an alternative procedure forpreparing compounds such as 16. In this case the imidazole aldehyde 21is condensed with a phosphonate hydantoin, such as 9A to afford theadduct 23. Equally applicable would be a hydantoin phosphonatecontaining a combination of R₄ and R₁ substituents. Compound 23 istreated with a reactive electrophile and a base, such as butyl iodideand K₂ CO₃ respectively, to afford Compound 24. This intermediate thenupon treatment with a reactive electrophile affords 16 with goodregioselectivity. More specifically the hydantoin 9A is condensed with21 in CH₂ Cl₂ using DBU as a base at room temperature. The Z-isomer isseparated, alkylated at N-3, and treated with thetrifluoromethanesulphone derived from ethyl 4-hydrozymethyl benzoate at-78° C. in CH₂ Cl₂. The reaction mixture is allowed to warm slowly toroom temperature and the product 16 isolated upon removal of theprotecting group.

A number of substituents are tolerated at position Y, as shown in SchemeVII. The condensation of a substituted phosphonate hydantoin withCompounds 24 through 28 is effected by the addition of base in anappropriate solvent. Typical conditions include the use of DBU in CH₂Cl₂ at room temperature as well as NaH in methanol. The reaction time istypically several hours with a greater portion of the Z isomer beingformed when DBU is used as the base. Where the substrate contains anacidic hydrogen, as in Compound 29, a further equivalent of base isrequired for efficient conversion. ##STR17##

The compounds of Formula I or Ia are antagonists of angiotensin II.Dudley, D. T., et al, Molecular Pharmacology 1990; 38:370-377 reportedthe existence of 2 subclasses of angiotensin II binding sites in rabbitadrenal gland and uterus and in the rat liver which differ in theirtissue distribution and affinity for various peptide and nonpeptideligands. Thus, the compounds of Formula I or Ia were tested for theirability to inhibit [³ H]angiotensin II binding to rat liver membranes(AT₁ test) according to the methods described by Dudley, D. T., et al,Molecular Pharmacology 1990; 38:370-7. Compounds of Formula I or Ia areactive in the AT₁ test with IC₅₀ values as in Table I below.

It is well established that compounds which antagonize the effect ofangiotensin II at the AT₁ receptor have value for treatment ofhypertension and heart failure.

                  TABLE I                                                         ______________________________________                                        Example      AT.sub.1 IC.sub.50 (nM)                                          ______________________________________                                         1a          2.7                                                               1b          2.82                                                              2a          9.4                                                               2b          8.8                                                               3a          172                                                               3b          83.8                                                              4a          11.2                                                              4b          4.17                                                              5           643                                                               6a          2.97                                                              6b          1.43                                                              15a         10.9                                                              15b         10.3                                                              16a         5.45                                                              16b         6.92                                                              17a         98.3                                                              17b         49.5                                                              18          21                                                                20a         3.36                                                              20b         2.47                                                              21a         111                                                               21b         89.3                                                              22          1.67                                                              23          3.39                                                              24          10.3                                                              25          6.39                                                              26a         2.63                                                              26b         2.22                                                              29          >1000                                                             32a         178                                                               32b         1170                                                              33          8.49                                                              35          40.2                                                              36          12.4                                                              37          14.3                                                              38          16.9                                                              39          159                                                               40          4.78                                                              41          30.9                                                              42          884                                                               43          3.33                                                              44          41.7                                                              47          >1000                                                             48          14.6                                                              49          9.48                                                              50          26.6                                                              51          5.33                                                              53          >1000                                                             54          29.5                                                              55          12.8                                                              56          47.8                                                              57          260                                                               58          5.81                                                              59          1.21                                                              60          2.63                                                              61          59.8                                                              62          1.21                                                              63          5.08                                                              64          4.30                                                              65          200                                                               66          17.6                                                              67          3.39                                                              68          4.2                                                               69          198                                                               70          104                                                               71a         3.21                                                              71b         4.18                                                              72          23.9                                                              73          1.3                                                               74          0.6                                                               75          0.64                                                              76a         3.36                                                              76b         2.48                                                              77          17.8                                                              78          21.9                                                              79          14.5                                                              80          14.6                                                              81          25.4                                                              82          7.96                                                              83          >1000                                                             84          124                                                               85          1.86                                                              86          4.58                                                              87a         10.0                                                              87b         7.32                                                              88a         276                                                               88b         528                                                               89          2.59                                                              90          20.9                                                              91          1.37                                                              92          2.72                                                              93          5.51                                                              94          8.57                                                              95          2.67                                                              96a         15.9                                                              96b         9.86                                                              97a         700                                                               97b         500                                                               98          377                                                               99          135                                                              101          35.7                                                             102          >1000                                                            103          120                                                              104          >1000                                                            105          1.47                                                             106          10.1                                                             107          1450                                                             108          8.47                                                             109          11.1                                                             110          2.47                                                             111          70.0                                                             112          6.44                                                             113          18.3                                                             ______________________________________                                    

Also, the compounds of Formula I or Ia were tested for functionalactivity in vitro. Thus, the compounds of the present invention weretested for their ability to antagonize angiotensin II inducedcontractions in rabbit aortic rings according to the method described byDudley D. T., et al, Molecular Pharmacology 1990; 38:370-7. Theaforementioned test methods are incorporated herein by reference.Compounds of Formula I or Ia are active in this in vitro functionalassay with IC₅₀ values ranging from 1×10⁻¹⁰ to 1×10⁻⁶ M.

Finally, the compounds of Formula I were tested in vivo for bloodpressure lowering effects in renal hypertensive rats (2-kidney, 1-clipGoldblatt model) according to the method described by S. Sen, et al, inHypertension 1979; 1:427-34 and in Clin. Soc. 1979; 57:53-62.

Illustrative of the in vivo antihypertensive activity for compounds ofFormula I or Ia is the data for Example 1a. This compound lowers bloodpressure by ≧50 mm Hg and is efficacious for more than 24 hours with asingle oral dose of 100 mg/kg in the renal hypertensive rat. FurthermoreExample 73 lowers blood pressure by ≧30 mm Hg and is efficacious formore than 24 hours with a single oral dose of 30 mg/kg in the renalhypertensive rat.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. It will beobvious to those skilled in the art that the following dosage forms maycompromise as the active component, either a compound of Formula I or Iaor a corresponding pharmaceutically acceptable salt of a compound ofFormula I or Ia.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from 5% to 10% to about 70%of the active compound. Suitable carriers are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term "preparation" isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient-sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing, and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 100 mg, preferably 0.5 mg to 100 mg,according to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as antihypertensive agents, the compounds utilized inthe pharmaceutical method of this invention are administered at theinitial dosage of about 0.1 mg to about 50 mg per kilogram daily. Adaily dose range of about 0.5 mg to about 30 mg per kilogram ispreferred. The dosages, however, may e varied depending upon therequirements of the patient, the severity of the condition beingtreated, and the compound being employed. Determination of the properdosage for a particular situation is within the skill of the art.Generally, treatment is initiated with smaller dosages which are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

The following examples are illustrative of the final products of theinstant invention as well as illustrative of intermediate compoundsuseful in preparing final compounds. They are not intended to limit thescope of the invention.

EXAMPLE 1a AND 1b 1a(E)-4-[[2-Butyl-5[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1-H-imidazol-1-yl]methylbenzoicacid

A solution of 3.44 g (0.012 mole) of2-butyl-1-(4-carboxybenzyl)-5-formylimidazole, 2.40 g (0.016 mole) of1-butylhydantoin, 25.92 g (0.071 mole) of 25% tetramethylammoniumhydroxide-in-methanol and 12 mL of water is heated with stirring with anoil bath (bath temperature 135°-150° C.), allowing the methanol todistill over. After ca. 1/2 hour, the pot temperature is ca. 115°-120°C. The temperature is maintained 115°-120° C. for 15 minutes. Thereaction solution is cooled to 70° C. and 5.04 g (0.084 mole) of glacialacetic acid and then ca. 100 mL of water are added to precipitate themixed cis (Z) and trans (E) isomers. Separation with 200 mL of methanol,cooling, and filtering off the least soluble (E) isomer.Recrystallization of the (E) isomer is effected by dissolution in 50%methanol-methylene chloride and concentration to remove methylenechloride. The separated pale yellow crystals are filtered; mp 287°-289°C.; tlc (2:10 MeOH--CHCl₃), 1 spot, Rf 0.4; nmr (DMSO--d₆), vinyl protonat δ 5.86 ppm; MS (CI) 425.1 (M⁺ +1).

Analysis calculated for C₂₃ H₂₈ N₄ O₄ ·0.25H₂ O: C, 64.39; H, 6.70; N,13.06.

Found: C, 64.36; H, 6.58; N, 12.87.

1b(Z)-4-[[2-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoicacid

The more soluble (Z) isomer is isolated from the methanol filtrate ofExample 1a. The filtrate is concentrated. The residue is heated with2-propanol to the boiling point. The insolubles are filtered. Isopropylether is added to the filtrate to precipitate some mixed isomers. Afterfiltration and concentration the residue is recrystallized from ethylacetate-isopropyl ether to give pure (Z) isomer; mp 163°-165° C.; nmr(DMSO--d₆), single vinyl proton at δ 6.25 ppm; MS (CI) 425 (M⁺ +1).

Analysis calculated for C₂₃ H₂₈ N₄ O₄ ·0.25H₂ O: C, 64.39; H, 6.70; N,13.06.

Found: C, 64.36; H, 6.58; N, 12.87.

EXAMPLE 2a AND 2b 2a(E)-4-[[2-Butyl-5-[[2,5-dioxo-3-(3-methylbutyl)-4-imidazolidinylidene]methyl]-1H-imidazole-1-yl]methyl]benzoicacid

This compound is prepared by a procedure similar to Example 1, startingfrom 1-isoamyl hydantoin. Pure (E) isomer is isolated as the leastsoluble isomer;

mp 288°-290° C.; nmr (DMSO--d₆), vinyl proton at 5.84 ppm;

MS (CI) 439 (M⁺ +1).

Analysis calculated for C₂₄ H₃₀ N₄ O₄ : C, 65.73; H, 6.90; N, 12.78.

Found: C, 65.42; H, 56.88; N, 12.86.

2b(Z)-4-[[2-Butyl-5-[[2,5-dioxo-3-(3-methylbutyl)-4-imidazolidinylidene]methyl]-1H-imidazole-1-yl]methyl]benzoicacid

This isomer is isolated as the most soluble isomer in Example 2a. Itspurity is 89.6% (Z) isomer and 8.2% (E) isomer as indicated by HPLCanalysis and by integration of the vinyl proton of the major (Z) isomerat 6.25 ppm vs the minor (E) isomer at 5.84 ppm in the nmr (DMSO--d₆);mp 143°-146° C.

Analysis calculated for C₂₄ H₃₀ N₄ O₄₃ ·0.75H₂ O: C, 63.77; H, 7.03; N,12.40.

Found: C, 63.79; H, 7.69; N, 12.76.

EXAMPLE 3A and 3B 3a(E)-4-[[2-Butyl-5-[(2,5-dioxo-3-methyl-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methylbenzoicacid

This compound is prepared by a procedure similar to Example 1 exceptthat the starting materials are the ester derivative,2-butyl-1-(4-carbomethoxybenzyl)-5-formylimidazole, and1-methylhydantoin. The crude mixed isomer products are purified andseparated by silica gel column chromatography, eluting with 0.1:1.5:10glacial acetic acid-methanol-chloroform. The "slow" moving material isthe (E) isomer; tlc (0.1:2:10 acetic acid-methanol-chloroform system) 1spot, Rf 0.5; mp 219°-221° C.; nmr (DMSO--d.sub.), vinyl proton at δ5.96 ppm; MS (CI) 383 (M⁺ +1).

Analysis calculated for C₂₀ H₂₂ N₄ O₄ ·0.25H₂ O: C, 62.08; H, 5.86; N,14.48.

Found: C, 62.04; H, 5.96; N, 14.33.

3b(Z)-4-[[2-Butyl-5-[(2,5-dioxo-3-methyl-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoicacid

The "fast" moving isomer isolated from chromatography in the aboveprocedure, 3a, is identified as the pure (Z) isomer; tlc (0.1:2:10acetic acid-methanol-chloroform system), 1 spot, Rf 0.7; mp 248°-250°C.; nmr (DMSO--d₆), vinyl proton at δ 6.19 ppm; MS (CI) 383 (M⁺ +1).

Analysis calculated for C₂₀ H₂₂ N₄ O₄ ·0.5H₂ O: C, 61.37; H, 5.92; N,14.32.

Found: C, 61.09; H, 5.98; N, 14.26.

EXAMPLE 4a AND 4b 4a(E)-4-[[2-Butyl-5-[(2,5-dioxo-3-(phenylmethyl)-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid

This compound is prepared by a procedure similar to Example 3 startingwith 1-benzylhydantoin. Pure (E) isomer is isolated as the compound thatis least soluble in methanol; mp 297°-298° C.; nmr (DMSO--d₆) singlevinyl proton at δ 5.90 ppm; MS (CI) 459 (M⁺ +1).

Analysis calculated for C₂₆ H₂₆ N₄ O₄ ·0.5H₂ O: C, 66.79; H, 5.82; N,11.99.

Found: C, 66.71; H, 5.94; N, 12.04.

4b(Z)-4-[[2-Butyl-5-[(2,5-dioxo-3-(phenylmethyl)-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid

This isomer (Z) is isolated as the most soluble isomer in the aboveExample 4a. Its purity is estimated to be 85% (Z) and 15% (E) isomer asindicated by the ratio of the vinyl proton integrations in the nmr(DMSO--d₆); vinyl proton for (Z) isomer at δ 6.05 ppm; MS (CI) 459 (M⁺+1).

Analysis calculated for C₂₆ H₂₆ N₄ O₄ ·0.75H₂ O: C, 66.15; H, 5.88; N,11.87.

Found: C, 65.96; H, 5.87; N, 11.79.

EXAMPLE 5(E)-4-[[2-Butyl-5-[(2,5-dioxo-3-phenyl-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid

This compound is prepared by a procedure similar to Example 1. Thecompound least soluble in 2-propanol is identified as the pure(E)-isomer; mp 286°-290° C.; tlc (1:10 methanol-chloroform) 1 spot, Rf0.2; nmr (DMSO--d₆) single vinyl proton at δ 5.89 ppm; MS (CI) 445 (M⁺+1).

Analysis calculated for C₂₅ H₂₄ N₄ O₄ ·H₂ O: C, 64.92; H, 5.67; N,12.11.

Found: C, 65.41; H, 5.47; N, 12.23.

EXAMPLE 6a AND 6b 6a(E)-4-[[2-Butyl-5-[[2,5-dioxo-3-((2-thienyl)methyl)-4-imidazolidinylidene]methyl]-1H-imidazole-1-yl]methyl]benzoicacid

This compound is prepared by a procedure similar to Example 3 startingwith 1-(2-thienylmethyl)hydantoin. Pure (E) isomer is isolated as thecompound that is least soluble in methanol; mp 297°-299° C.; tlc(0.1:5:20 acetic acid-methanol-chloroform), 1 spot, Rf 0.6; nmr(DMSO--d₆) single vinyl proton at δ 6.13 ppm; MS (CI) 465 (M⁺ +1).

Analysis calculated for C₂₄ H₂₄ N₄ O₄ S·0.25H₂ O: C, 61.32; H, 5.47; N,11.92.

Found: C, 61.30; H, 5.21; N, 11.95.

6b(Z)-4-[[2-Butyl-5-[[2,5-dioxo-3-((2-thienyl)methyl)-4-imidazolidinylidene]-methyl]-1-yl]methyl]benzoicacid

This isomer (Z) is isolated as the most soluble isomer int he aboveExample 6a. It is recrystallized from ethylacetate to give pure (Z)isomer; mp 140°-145° C.; tlc (0.1:5:20 acetic acid-methanolchloroform),1 spot, Rf 0.8 nmr (DMSO--d₆), single vinyl proton at 6.16 ppm. MS (CI)465 (M⁺ +1).

Analysis calculated for C₂₄ H₂₄ N₄ O₄ S·0.25 C₄ H₈ O₂ : C, 61.70; H,5.39; N, 11.52.

Found: C, 61.43; H, 5.45; N, 11.69.

EXAMPLE 7 2-Butyl-1-(4-carboxybenzyl)-5-formylimidazole

A solution of 3.00 g (0.01 mole) of2-butyl-1-(4-carbomethoxybenzyl)-5-formylimidazole in 100 mL of methanoland 15 mL (0.03 mole) of 2N sodium hydroxide is heated to the boilingpoint, allowing methanol to distill over. After 1 hour, the pottemperature is 85° C. Water (30 mL) and then 30 mL of 1N hydrochloricacid are added to precipitate a gum. This crystallized; wt 2.40 g.Recrystallization from ethyl acetate gives 1.30 g of product; mp146°-148° C.; tlc (1:10 MeOH-CHCl₃), 1 spot, Rf 0.3; MS (CI) 287 (M⁺+1).

Analysis calculated for C₁₆ H₁₈ N₂ O₃ : C, 67.12; H, 6.34; N, 9.78.

Found: C, 67.14; H, 6.28; N, 9.72.

EXAMPLE J8 2-Butyl-1-(4-carbomethoxybenzyl)-5-formylimidazole (J. Med.Chem. 1991; 34:1514-17)

A solution of 1.00 g (0.003 mole) of2-butyl-1-(4-carbomethoxybenzyl)-4-chloro-5-formylimidazole in 75 mL ofmethanol is reduced at low pressure with hydrogen and 0.30 g of 5%Pd/carbon in the presence of 0.30 g of potassium acetate to giveproduct; mp 62°-64° C.; tlc (1:1 hexane-ethyl acetate) 1 spot, Rf 0.2;MS (CI) 301 (M⁺ +1).

EXAMPLE 9 2-Butyl-1-(4-carbomethoxybenzyl)-4-chloro-5-formylimidazole(J. Med. Chem. 1991; 34:1514-17).

A solution of 17.50 g (0.098 mole) of 2-butyl-4-chloro-5-formylimidazole(U.S. Pat. No. 4,355,040) in 855 mL of DMF is treated with 91.65 g (0.28mole) of cesium carbonate and the mixture is stirred at room temperaturefor 10 minutes. A solution of 22.56 g (0.099 mole) of methyl4-(bromomethyl)benzoate in 270 mL of DMF is added and the mixture isstirred for 4 hours at room temperature. The cesium salts are filteredand the DMF filtrate is concentrated at reduced pressure. The crudeproduct is purified by silica gel chromatography, eluting with methylenechloride, and then 1:7 ethyl acetate/methylene chloride, obtaining 23.16g (74%) of pure product; mp 96°-98° C.; tlc (1:1 hexane-ethyl acetate),1 spot, Rf 0.7; MS (CI), 335 (M⁺).

EXAMPLE 10 1-Butyl hydantoin (Org. Mass. Spectrometry 1971; 5:551-3).

A quantity of 24.4 g (0.30 mole) of potassium cyanate is addedportionwise, at room temperature, to a stirred solution of 31.80 g (0.20mole) of ethyl N-butylglycinate in 220 mL (0.22 mole) of 1N hydrochloricacid. The solution is warmed to ca. 90° C. (at ca. 50° C. an oilseparates). After 10 minutes at 90° C., concentrated hydrochloric acid(250 mL) is cautiously added over 2 minutes and the resulting solutionis heated at 90°-100° C. for 1/2 hour. The solution is concentrated atreduced pressure to dryness. The last amounts of water are chased byaddition and removal of 3×100 mL of absolute ethanol. The residue isextracted with 400 mL 50% ethanolmethylene chloride. The inorganics arefiltered and the filtrate is concentrated to dryness. Trituration of theresidue with 100 mL of water and filtration gives pure 1-butylhydantoinin 68% yield; mp 90°-92° C.; MS (EI) 156.1 (M⁺).

Analysis calculated for C₇ H₁₂ N₂ O₂ : C, 53.83; H, 7.69; N, 17.99.

Found: C, 53.88; H, 7.80; N, 17.85.

EXAMPLE 11 1-Isoamylhydantoin

The compound is prepared by the procedure outlined in Example 10; mp84°-85° C.; MS (EI) 170 (M⁺).

Analysis calculated for C₈ H₁₄ N₂ O₂ : C, 56.45; H, 8.29; N, 16.46.

Found: C, 56.84; H, 8.38; N, 16.34.

EXAMPLE 12 1-Benzylhydantoin

This compound is prepared by the procedure outlined in Example 10; mp139°-140° C.; MS (EI) 190 (M⁺).

Analysis calculated for C₁₀ H₁₀ N₂ O₂ ·0.1H₂ O: C, 62.55; H, 5.35; N,14.59.

Found: C, 62.48; H, 5.56; N, 14.36.

EXAMPLE 13 1-(2-Thienylmethyl)hydantoin

This compound is prepared by a procedure similar to that in Example 10;mp 140°-142° C.; MS (EI) 196 (M⁺).

Analysis calculated for C₈ H₈ N₂ O₂ S: C, 48.97; H, 4.11; N, 14.28.

Found: C, 49.00; H, 4.05; N, 14.19.

EXAMPLE 14 1-Phenylhydantoin

This compound is prepared by a procedure similar to that in Example 10;mp 193°-194° C.; MS (EI) 176 (M⁺).

Analysis calculated for C₉ H₈ N₂ O₂ : C, 61.36; H, 4.58; N, 15.90.

Found: C, 61.38; H, 4.52; N, 15.92.

EXAMPLE 15a AND 15b 15a (Condition A)(E)-4-[[2-Butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoic acid, methyl ester

To a mixture of 1-butyl-2,4-dioxomidazolidine-5-phosphonate (680 mg,2.41 mmol) and 2-butyl-1-(4-carbomethoxybenzyl)-5-formylimidazole (490mg, 1.67 mmol) in methanol (15 mL) is cautiously added sodium hydride80% dispersion in oil. The mixture is stirred for 1 hour at roomtemperature. Acetic acid (0.30 mL, 5.24 mmol) is added dropwise whichcauses the yellow solution to lighten. The mixture is evaporated invacuo. This mixture is extracted into dichloromethane, washed withwater, and dried over sodium sulfate. NMR analysis of this reactionmixture indicates a 1:1 mixture of E- and Z-isomers. Chromatography onsilica gel eluting with 97 CHCl₃ 3 MeOH affords pure Z- and thenE-isomer. NMR on (E) isomer: (CDCl₃) single vinyl proton at δ 5.60 ppm.E-isomer.

Analysis calculated for C₂₄ H₃₀ N₄ O₄ : C, 65.73; H, 6.90; N, 12.78.

Found: C, 65.50; H, 6.87; N, 12.66.

MS (EI) 438.

15b (Conditions A)(Z)-4-[[2-Butyl-5-[(3-Butyl-2,5-Dioxo-4-Imidazolidinylidene)Methyl]-1H-Imidazole-1-yl]Methyl]Benzoic Acid, Methyl Ester

The Z-isomer is isolated as described in 15a; NMR (CDCl₃), single vinylproton at δ 6.32 ppm.

Analysis calculated for C₂₄ H₃₀ N₄ O₄ : C, 65.73; H, 6.90; N, 12.78.

Found: C, 65.54; H, 6.85; N, 12.53.

EXAMPLE 15a AND 15b (Conditions B)

To diethyl 1-butyl-2,4-dioxoimidazolidine-5-phosphonate (590 mg, 2.1mmol) in acetonitrile (5 mL) is added lithium chloride (79 mg, 1.86mmol) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (277 μL, 1.85 mmol). Ayellow solution forms within 5 minutes.2-Butyl-1-(4-carbomethoxybenzyl)-5-formylimidazole (461 mg, 1.54 mmol)is added. After 10 minutes, lithium chloride (79 mg, 1.86 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (277 μL, 1.85 mmol) are again added.A precipitate develops. Upon stirring at room temperature for 16 hours,a wine-red solution remains. This mixture is concentrated in vacuo andapplied directly to a silica gel column. Eluting with 95 CHCl₃ 5 MeOHaffords, in order of increasing polarity, the Z-isomer (441 mg, 65%) andthen the E-isomer (96 mg, 14%) which had identical spectralcharacteristics as the compounds produced by Conditions A.

EXAMPLE 16a AND 16b 16a(E)-4-[[2-Butyl-5-[[2,5-Dioxo-3-((2-Thienyl)Methyl)-4-Imidazolidinylidene]Methyl]-1H-Imidazole-1-yl]Methyl]BenzoicAcid, Methyl Ester

A mixture of the (E) carboxylic acid derivative from Example 6 a and 30mL of methanol is treated with a stream of hydrogen chloride gas,allowing the temperature to rise. The resulting solution is allowed tostand at room temperature overnight. The solution is concentrated to ca.1/2 volume and excess saturated NaHCO₃ solution is added to precipitatepure crystalline product; mp 209°-210° C.; tlc (1:10 MeOH--CHCl₃) 1spot, Rf 0.5; MS (CI) 479 (M⁺ +1).

Analysis calculated for C₂₅ H₂₆ N₄ O₄ S·0.1H₂ O: C, 61.89; H, 5.44; N,11.55.

Found: C, 62.20; H, 5.36; N, 11.43.

16b(Z)-4-[[2-Butyl-5-[[2,5-Dioxo-3-((2-Thienyl)Methyl)-4-Imidazolidinylidene]Methyl]-1H-Imidazole-1-yl]Methyl]BenzoicAcid, Methyl Ester

This compound is prepared as in Example 16a from the (Z) carboxylic andderivative from Example 6b; mp 164°-165° C.; tlc (1:10 MeOH--CHCl₃) 1spot, Rf 0.6; MS (CI) 479 (M⁺ +1).

Analysis calculated for C₂₅ H₂₆ N₄ O₄ S: C, 62.74; H, 5.48; N, 11.71.

Found: C, 63.00; H, 5.23; N, 11.47.

17a(E)-4-[[2-Butyl-5-[[2,5-Dioxo-3-(4-Hydroxybutyl)-4-Imidazolidinylidene]Ethyl]-1H-Imidazole-1-yl]Methyl]BenzoicAcid, Methyl Ester

This compound is prepared as with the butyl hydantoin derivatives inExample 1a and then esterified with diazomethane. E- and Z-isomers areseparated by flash chromatography on silica gel (CHCl₃ --MeOH, 96:4); mpof (E) isomer 167°-170° C.; NMR (CDCl₃) single vinyl proton at δ 5.62;MS (CI) 455 (M⁺ +1).

Analysis calculated for C₂₄ H₃₀ N₄ O₅ : C, 63.42; H, 6.65; N, 12.33.

Found: C, 63.25; H, 6.67; N, 12.22.

17b (Z)-4-[[2-Butyl-5-[[2,5-Dioxo-3-(4-Hydroxybutyl)-4-Imidazolidinylidene]Methyl]-1H-Imidazole-1-yl]Methyl]BenzoicAcid, Methyl Ester

This compound is isolated from the chromatography in the above Example17a; mp 76°-86° C.; MS (CI) 455 (M⁺ +1).

Analysis calculated for C₂₄ H₃₀ N₄ O₅ ·0.1CH₃ OH: C, 63.24; H, 6.69; N,12.24.

Found: C, 63.65; H, 6.91; N, 11.83.

EXAMPLE 18 (E)-4-[[2-Propyl-5-[(3-Butyl-1-Methyl-2,5-Dioxo-4-Imidazolidinylidene)-Methyl]-1H-Imidazole-1-yl]Methyl]BenzoicAcid, Methyl Ester

A solution of 0.082 g (0.17 mmol) of the 2-propyl (E) isomerhydrochloride prepared similarly to Example 15a, and 0.024 g (0.17 mmol)of methyl iodide in 0.50 mL of DMF is cooled in an ice bath. Withstirring, 0.5 g anhydrous potassium carbonate is added. The mixture isremoved from the ice bath and stirred at room temperature for 1 hour. Tocomplete the reaction, another 0.024 g of methyl iodide is added and themixture is stirred for another 1 hour. Water (5 mL) is added toprecipitate crude product. Recrystallization from ether gives pureN-methyl derivative; mp 113°-114° C.; tlc (1:10 MeOH--CHCl₃) 1 spot,RF0.6; MS (CI) 439 (M⁺ +1).

EXAMPLE 19 3-Butyl-2,5-Dioxo-Imidazolidene-4-Phosphinic Acid, DiethylEster

To a solution of 1-butylhydantoin (3.5 g, 0.022 moles) in glacial aceticacid (20 mL) at 90°-100° C. is added bromine (1.22 mL, 0.024 moles) inacetic acid (10 mL) batchwise; at such a rate that the initialorange-red color discharges to a yellowish solution. This addition ratetakes about 5 minutes. The solution is stirred at 90°-100° C. for afurther 60 minutes. 1H Analysis of the reaction mixture indicatesincomplete conversion. A further amount of bromine (0.3 mL) is added andthe solution is refluxed for 1 hour and then stirred for 16 hours atroom temperature. Concentration in vacuo from toluene affords a viscousoil (5.5 g). This oil is dissolved in diethyl ether and treated withtriethyl phosphite (3.7 mL, 0.022 moles). The solution is stirred for 16hours at room temperature. The mixture is evaporated in vacuo and therequired product isolated by chromatography on silica gel, eluting with95 CHCl₃ --5 MeOH. This viscous oil contains small amounts of animpurity but is sufficiently pure to be used in subsequent reactions;NMR (1H, CDCl₃) δ 8.86 (1H, br s), 4.30 (7H, m), 3.86 (1H, m), 3.38 (1H,m), 1.60 (2H, m), 1.35 (9H, m), 0.89 (3H, m); MS (CI) 293.

EXAMPLES 20a AND 20b 20aE-4-[[2-Butyl-5-[[3-[(4-Chlorophenyl)Methyl]-2,5-Dioxo-4-Imidazolidinylidene]Methyl]-1H-Imidazol-1-yl]Methyl]BenzoicAcid

This compound is prepared by a procedure similar to example 1, startingfrom 1-[(4-chlorophenyl)methyl]-2,4-imidazolidinedione. Pure E isomer isisolated as the least soluble isomer in 2-propanol; mp 248°-250° C.; nmr(DMSO--d₆), vinyl proton at 5.89 ppm; MS (CI) 493 (m+).

Anal. Calcd. for C₂₆ H₂₅ ClN₄ O₄. 0.25 H₂ O: C, 62.77; H, 5.17; N,11.26.

Found: C, 62.84; H, 5.08; N, 11.12.

20bZ-4-[[2-Butyl-5-[[3-[(4-Chlorophenyl)Methyl]-2,5-Dioxo-4-Imidazolidinylidene]Methyl]-1H-Imidazol-1-yl]Methyl]BenzoicAcid

This compound is isolated as the most soluble isomer in Example 20a. Itis purified by silica gel chromatography, eluting with 1:5:40 aceticacid-methanol-chloroform to give pure faster moving Z isomer; mp225°-227° C.; nmr (DMSO--d₆), vinyl proton at 6.09 ppm; MS (CI) 493(m⁺).

Anal. Calcd. for C₂₆ H₂₅ ClN₄ O₄ : C, 63.35; H, 5.11; N, 11.37.

Found: C, 63.01; H, 5.09; N, 11.20.

EXAMPLES 21a AND 21b 21aE-4-[[2-Butyl-5-[[3-[(3,4-Dimethoxyphenyl)Methyl]-2,5-Dioxo-4-Imidazolidinylidene]Methyl]-1H-Imidazol-1-yl]Methyl]BenzoicAcid

This compound is prepared by a procedure similar to Example 1 startingfrom 1-[3,4-dimethoxyphenyl) methyl]-2,4-imidazolidinedione. Pure Eisomer is isolated as the least soluble isomer in methanol; mp 266°-267°C.;

NMR (DMSO--d₆), vinyl proton at 5.97 ppm; MS (CI), 519 (m⁺ +1).

Anal. Calcd. for C₂₈ H₃₀ N₄ O₆ : C, 64.85; H, 5.83; N, 10.80.

Found: C, 64.82; H, 6.03; N, 10.93.

21bZ-4-[[2-Butyl-5-[[3-[3,4-Dimethoxyphenyl)Methyl]-2,5-Dioxo-4Imidazolidinylidene]Methyl]-1H-Imidazol-1-yl]Methyl]BenzoicAcid

This compound is isolated as the most soluble isomer in Example 21a. Itis purified by recrystallization from ethyl acetate; mp 225°-226° C.;

NMR (DMSO--d₆), vinyl proton at 6.14 ppm; MS (CI) 519 (m⁺ +1).

Anal. Calcd. for C₂₈ H₃₀ N₄ O₆ : C, 64.85; H, 5.83; N, 10.80.

Found: C, 64.62; H, 5.94 N, 10.73.

EXAMPLE 22 MethylZ-4-[[2-Butyl-5-[(1,3-Dibutyl-2,5-Dioxo-4-imidazolidinylidene)Methyl]-1H-Imidazol-1-yl]Methyl]Benzoate Monohydrochloride

A mixture of 0.220 g (10.5 mmol) of the Z-isomer NH hydantoin fromExample 15b, 0.50 mL of DMF, 0.20 g of powdered potassium carbonate and0.101 g (0.5 mmol) of butyl iodide is stirred at 25° C. for 2 hours.Crushed ice is added to precipitate the gummy product. The aqueous DMFis decantered and the gum is extracted into 15 mL of ether. The ethersolution is washed with water, dried (K₂ CO₃) and treated with hydrogenchloride to precipitate a gummy hydrochloride salt which crystallizes oninducement. Recrystallization form 2-propanol-ether gives pure product;mp 153°-155° C.; NMR (DMSO--d₆), vinyl proton at 6.26 ppm; MS (CI) 495.5(M⁺ +1).

Anal. Calcd. for C₂₈ H₃₈ N₄ O₄ HCl: C, 63.32; H, 7.40; N, 10.55.

Found: C, 63.51; H, 7.58; N, 10.36.

EXAMPLE 23 Methyl Z-4-[[2-Butyl-5-[[1-Butyl-2,5-Dioxo-3-(2-Thienylmethyl)-4-Imidazolidinylidene]Methyl]-1H-Imidazol-1-yl]Methyl]BenzoateMonohydrochloride

This compound is prepared from the NH hydantoin derivative of Example16b by an alkylation procedure similar to that in Example 22; mp ofhydrochloride salt, 185°-187° C.;

NMR (DMSO--d₆), vinyl proton at 6.07 ppm; MS (CI) 535 (m⁺ +1).

Anal. Calcd. for C₂₉ H₃₄ N₄ O₄ S HCl: C, 60.99; H, 6.18; N, 9.81.

Found: C, 60.69; H, 6.16; N, 9.69.

EXAMPLE 24 Methyl E-4-[[2-Butyl-5-[[(1-Butyl-2,5-Dioxo-3-(2-Thienylmethyl)-4-Imidazolidinylidene]Methyl]-1H-Imidazol-1-yl]Methyl]BenzoateMonohydrochloride

This compound is prepared form the NH hydantoin derivative of Example16a by an alkylation procedure similar to that in Example 22; mp209°-211° C.;

NMR (DMSO--d₆), vinyl proton at 6.27 ppm; MS (CI) 535 (M⁺ +1).

Anal. Calcd. for C₂₉ H₃₄ N₄ O₄ HCl: C, 60.99; H, 6.18; N, 9.81.

Found: C, 60.69; H, 6.14; N, 9.53.

EXAMPLE 25Z-4-[[2-Butyl-5-[[1-Butyl-2,5-Dioxo-3-(2-Thienyl)Methyl]-4-Imidazolidinylidene]Methyl]-1H-Imidazol-1-yl]Methyl]BenzoicAcid

A solution of 0.174 g (0.30 mmol) of the ester from Example 23, 4 mL ofmethanol and 2 mL of 3N hydrochloric acid is maintained at reflux for 3days. The volatiles are removed at reduced pressure and the crudeproduct is chromatographed eluting with 5% methanol-chloroform. Theproduct is isolated as a glassy foam; tlc (1:10 methanol chloroform) onespot, Rf 0.4;

NMR (DMSO--d₆), vinyl proton at 6.28 ppm; MS (CI) 521 (M⁺ +1).

Anal. Calcd. for C₂₈ H₃₂ N₄ O₄ S: C, 64.59; H, 6.20; N, 10.76.

Found: C, 64.60; H, 6.19; N, 10.33.

EXAMPLES 26a AND 26b 26aE-1-[4-[[2-Butyl-5-[[2,5-Dioxo-3-(2-Thienylmethyl)-4-Imidazolidinylidene]Methyl]-1H-Imidazol-1-yl]Methyl]Phenyl]CyclopentanecarboxylicAcid

This compound is prepared by a procedure similar to that in Example 1.The product is isolated as the most soluble isomer in methanol in 70%purity nmr (DMSO--d₆) benzyl CH₂ at 5.36 ppm (major E isomer). Theimpurity is the minor Z isomer with benzyl CH₂ at 5.08 ppm; MS (CI) 533(M⁺ +1).

Anal. Calcd. for C₂₉ H₃₂ N₄ O₄ S: C, 65.39; H, 6.06; N, 10.52.

Found: C, 65.01; H, 5.99; N, 10.41.

26bZ-1-[4-[[2-Butyl-5-[[2,5-Dioxo-3-(2-Thienylmethyl)-4-Imidazolidinylidene]Methyl]-1H-Imidazol-1-yl]Methyl]Phenyl]CyclopentanecarboxylicAcid

This compound is isolated pure in Example 26a as the least solubleisomer in methanol; mp 261°-263° C.; NMR (DMSO--d₆) benzyl CH₂ at 5.08ppm; MS (CI) 533 (M⁺ +1).

Anal. Calcd. for C₂₉ H₃₂ N₄ O₄ S: C, 65.39; H, 6.06; N, 10.52.

Found: C, 65.14; H, 6.07; N, 10.35.

EXAMPLE 27 1-[(3,4-Dimethoxyphenyl)Methyl]-2,4-Imidazolidinedione

This compound is prepared by a procedure similar to that in Example 10;mp 130°-132° C. C; MS (CI) 250 (M+)

Anal. Calcd. for C₁₂ H₁₄ N₂ O₄ : C, 57.59; H, 5.64; N, 11.19.

Found: C, 57.46; H, 5.54; N, 11.19.

EXAMPLE 28 1-[(4-Chlorophenyl)Methyl]-2,4-Imidazolidinedione

This compound is prepared by a procedure similar to that in Example 10;mp 169°-171° C.; MS (EI) 224 (M+)

Anal. Calcd. for C₁₀ H₉ ClN₂ O₂ : C, 53.47; H, 4.04; N, 12.47.

Found: C, 53.50; H, 4.04; N, 12.48.

EXAMPLE 29 Methyl 4-[[2-Butyl-5-[(3-Butyl-2,5-Dioxo-4-Imidazolidinyl)Hydroxymethyl]-1H-Imidazol-1-yl]Methyl]Benzoate

To a suspension of 1-Butyl-2,4-imidazolidinedione (0.600 g, 4.17 mmol)in THF (15ml) at -78° C. is added lithium diisopropylamide (2.1 equiv.).After stirring for 20 minutes a solution of methyl4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoate (1.250 g, 4.17mmol) in THF (10 mL) is added dropwise over 10 minutes to form an orangesolution. This solution is stirred for a further 20 minutes at -78° C.and is then added to aqueous ammonium chloride. This mixture isevaporated in vacuo and then extracted into ethyl acetate. After washingwith water and then brine the solution is dried over Na₂ SO₄.Evaporation in vacuo and chromatography, eluant 5% methanol inchloroform, affords the required product. Recrystallized from ethylacetate containing traces of methanol.

Anal. Calcd. for C₂₄ H₃₁ N₄ O₅ : C, 63.14; H, 7.07; N, 12.27.

Found: C, 62.89; H, 7.07; N, 12.56.

EXAMPLE 30 MethylZ-4-[[2-Butyl-5-[(1-Butyl-2,5-Dioxo-4-Imidazolidinylidene)Methyl]-1H-Imidazol-1-yl]Methyl]Benzoate Monohydrochloride

To a solution of diethyl 2,5-dioxo-4-imidazolylphosphonate (0.600 g,2.53 mmol) in methanol (15mL) is cautiously added sodium hydride (80%)dispersion in oil) (0.152 g, 5.06 mmol) and stirred for 15 minutes toafford a pale yellow solution. To this is added methyl4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoate (0.730 g, 2.43mmol). This mixture is stirred for 2 hours in which time a yellowprecipitate develops. The reaction mixture is concentrated in vacuo andthen diluted with water (10 mL). 1N HCl (5 mL) is added to afford awhite precipitate. The precipitate is washed with water (20 mL) and thenwith ether (20 mL). This solid is the Z-isomer with the E-isomer evidentin the filtrate.

Anal. Calcd. for C₂₀ H₂₂ N₄ O₄. HCl: C, 57.34; H, 5.53; N, 13.38.

Found: C, 57.11; H, 5.45; N, 12.93.

MS (EI) 382.

EXAMPLE 31 Diethyl 1-Butyl-2,5-Dioxo-4-Imidazolylphosphonate

To a solution of diethyl 2,5-dioxo-4-imidazolylphosphonate (6.00 g,0.025 moles) in DMF (15 mL), under N₂, is added K₂ CO₃ (17.5 g, 0.127moles) and 1-iodobutane (2.9 mL, 0.025 moles). This mixture is stirredat room temperature for 16 hours and then the mixture is filtered andthe solid washed with ethyl acetate. The filtrate is concentrated invacuo, to afford a yellow oil which is redissolved in ethyl acetate andwashed with water and brine and then dried over MgSO₄. Evaporation ofsolvents under high vacuum affords the required product as a viscousyellow oil which solidifies on standing.

Anal. Calcd. for C₁₁ H_(21N2) O₅ P: C, 45.21; H, 7.24; N, 9.58.

Found: C, 44.83; H, 7.34; N, 9.84.

MS (EI) 293.

EXAMPLES 32A, 32b, 32c 32a MethylZ-4-[[2-Butyl-5-[(1-Butyl-2,5-Dioxo-4-Imidazolidinylidene)Methyl]-1H-Imidazol-1-yl]Methyl]Benzoate Monohydrochloride

To a solution of diethyl 1-butyl-2,5-dioxo-4-imidazolylphosphonate (1.47g, 5.00 mmol) in methylene chloride (8 mL) at 0° C. is added1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) (0.75 mL, 5.02 mmol). Theyellow solution is stirred for 5 minutes and then a solution of methyl4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoate (1.25 g, 4.17mmol) is added. This mixture is allowed to stir for 16 hours. Themixture is diluted with ethyl acetate containing 10% methylene chlorideand washed with 1M aqueous HCl (15 mL), water and then brine. Afterdrying over MgSO₄ the product is isolated as a yellow solid byconcentration in vacuo and treatment with ether. Chromatography of themother liquors after neutralizing with aqueous NaHCO3, eluting with 1%methanol in chloroform, affords a small amount of the correspondingE-isomer.

Data for Z-isomer as hydrochloride salt

Anal. Calcd. for C₂₄ H₃₀ N₄ O₄. HCl: C, 60.60; H, 6.58; N, 11.80.

Found: C, 60.25; H, 6.30; N, 11.48.

mp 197°-198° C.; MS (EI) 438.

Free base mp 172°-173° C. Recrystallized from ethyl acetate.

32b Methyl E-4-[[2-Butyl-5-[(1-Butyl-2,5-Dioxo-4-Imidazolidinylidene)Methyl]-1H-Imidazol-1-yl]Methyl]Benzoate

Anal. Calcd. for C₂₄ H₃₀ N₄ O₄. 0.33 H₂ O: C, 64.84; H, 6.95; N, 12.60.

Found: C, 64.55; H, 6.86; N, 12.46.

MS (EI) 438 mp 172°-174° C.

32c Alternative Procedure MethylZ-4-[[2-Butyl-5-[(1-Butyl-2,5-Dioxo-4-Imidazolidinylidene)Methyl]-1H-Imidazol-1-yl]Methyl]Benzoate

To a solution of diethyl 2,5-dioxo-4-imidazolylphosphonate (1.5 g, 0.33mmol) in DMF (4 mL) is added K₂ CO₃ and then 1-iodobutane (0.79 mL, 6.96mmol). This mixture is stirred for 16 hours at room temperature. To thisyellow mixture is added methyl4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoate (1.05 g, 3.5mmol). After 2 hours methylene chloride (10 mL) was added to aidstirring. The mixture was stirred for 16 hours. After diluting thereaction mixture with water it was extracted with ethyl acetate. Thisextract was washed with water and brine. The extract was dried overMgSO₄, filtered and then concentrated until crystallization wasapparent. The solid was collected and dried.

EXAMPLE 33 methylZ-4-[[2-Butyl-5-[(1,3-Dibutyl-2,5-Dioxo-4-Imidazolidinylidene)Methyl]-1H-Imidazol-1-yl]Methyl]Benzoate Monohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1yl]methyl]benzoate (0.475 g, 1.08 mmol) in DMF (6mL) is added K₂ CO₃ (0.750 g, 5.40 mmol). After stirring for 5 minutes1-iodobutane (0.150 mL, 1.32 mmol) is added. The mixture is stirred for16 hours, diluted with ethyl acetate and washed with water and brine andthen dried over MgSO₄. A viscous oil is obtained by evaporation of thesolvents in vacuo. This yellow oil is dissolved in ether and treatedwith ethereal HCl to precipitate a gummy solid. This gum is crystallizedfrom 2-propanol/ether.

Anal. Calcd. for C₂₈ H₃₈ N₄ O₄. HCl: C, 63.32; H, 7.40; N, 10.55.

Found: C, 63.36; H, 7.57; N, 10.66.

MS (EI) 494.

EXAMPLE 34 MethylZ-4-[[2-Butyl-5-[(1-Butyl-2,5-Dioxo-3-Pentyl-4-Imidazolidinylidene)Methyl]-1H-Imidazol-1-yl]Methyl]Benzoate Monohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1yl]methyl]benzoate (0.400 g, 0.92 mmol) in DMF (4mL) is added K₂ CO₃ (0.630 g, 4.57 mmol). After stirring for 5 minutes1-iodopentane (0.155 mL, 1.19 mmol) is added. The mixture is stirred for16 hours. After diluting with ethyl acetate and washing with water andbrine the solution is dried over MgSO₄. A viscous oil is obtained byevaporation of the solvents in vacuo. This yellow oil is dissolved inether and treated with ethereal HCl to precipitate a gummy solid. Thisgum is crystallized from 2-propanol/ether.

Anal. Calcd. for C₂₉ H₄₀ N₄ O₄. HCl: C, 63.89; H, 7.58; N, 10.28.

Found: C, 63.91; H, 7.26; N, 10.13.

mp 128°-130° C.; MS (EI) 508.

EXAMPLE 35 MethylZ-4-[[2-Butyl-5-[(1-Butyl-3-Hexyl-2,5-Dioxo-4-Imidazolidinylidene)Methyl]-1H-Imidazol-1yl]Methyl]Benzoate Monohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1yl]methyl]benzoate hydrochloride (0.450 g, 0.95mmol) in DMF (4 mL) is added K₂ CO₃ (0.800 g, 5.80 mmol). After stirringfor 5 minutes 1-iodohexane (0.190 mL, 1.29 mmol) is added. The mixtureis stirred for 16 hours, diluted with ethyl acetate, washed with waterand brine, and then dried over MgSO₄. A viscous oil is obtained byevaporation of the solvents in vacuo. This yellow oil is dissolved inether and treated with ethereal HCl to precipitate a gummy solid. Thisgum is triturated with pentane and ether to afford a pale yellow solid.

Anal. Calcd. for C₃₀ H₄₂ N₄ O₄. HCl: C, 64.33; H, 7.92; N, 10.00.

Found: C, 64.04; H, 7.61; N, 9.78.

mp 134°-135° C. MS (EI) 522.

EXAMPLE 36 MethylZ-4-[[2-Butyl-5-[(1-Butyl-2,5-Dioxo-3-(Phenylmethyl)-4-Imidazolidinylidene)Methyl]-1H-Imidazol-1-yl]Methyl]Benzoate Monohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (0.509 g, 1.16 mmol) in DMF (6mL) is added K2CO₃ (0.800 g, 5.80 mmol). After stirring for 5 minutesbenzylbromide (0.150 mL, 1.26 mmol) is added. The mixture is stirred for16 hours, diluted with ethyl acetate, washed with water and brine, andthen dried over MgSO₄. A viscous oil is obtained upon chromatography onsilica gel (eluant 1% methanol in chloroform) and evaporation of thesolvents in vacuo. This yellow oil is dissolved in ether and treatedwith ethereal HCl to afford a foamy solid upon evaporation in vacuo.

Anal. Calcd. for C₃₁ H₃₆ N₄ O₄. HCl. 1.25 H₂ O: C, 63.35; H, 6.78; N,9.53.

Found: C, 63.13; H, 6.83; N, 9.43.

mp 110°-113° C.; MS (EI) 528.

EXAMPLE 37 MethylZ-4-[[2-Butyl-5-[[1-Butyl-3-[[4-Methoxycarbonyl)Phenyl]Methyl]-2,5-Dioxo-4-Imidazolidinylidene]Methyl]-1H-Imidazol-1-yl]Methyl]BenzoateMonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (0.500 g, 1.14 mmol) in DMF (4mL) is added K₂ CO₃ (0.800 g, 5.80 mmol). After stirring for 5 minutesmethyl (4-bromomethyl)benzoate (0.275 g, 1.20 mmol) is added. Themixture is stirred for 16 hours, diluted with ethyl acetate, washed withwater and brine, and then dried over MgSO₄. A viscous oil is obtainedupon chromatography on silica gel (eluant 1% methanol in chloroform) andevaporation of the solvents in vacuo. This yellow oil is dissolved inether and treated with ethereal HCl to precipitate a gummy solid. Thisgum is crystallized from 2-propanol/ether.

Anal. Calcd. for C₃₃ H₃₈ N₄ O₆. HCl: C, 64.13; H, 5.54; N, 9.06.

Found: C, 63.44; H, 6.31; N, 8.79.

mp 165°-167° C.; MS (EI) 528.

EXAMPLE 38 Methyl Z-4-[[2-butyl-5-[[1-butyl-3-[(4-nitrophenyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemono hydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.370 g, 0.84 mmol) in DMF (4 mL) is added K₂ CO₃ (0.580 g, 420 mmol).After stirring for 5 minutes 4-nitrobenzylbromide (0.218 g, 1.01 mmol)is added. The mixture is stirred for 16 hours, diluted with ethylacetate, washed with water and brine, and then dried over MgSO₄. Aviscous oil is obtained upon chromatography on silica gel (eluant 1%methanol in chloroform) and evaporation of the solvents in vacuo. Thisyellow oil is dissolved in ether and treated with ethereal HCl to afforda foamy solid upon evaporation in vacuo.

Anal. Calcd. for C₃₁ H₃₅ N₅ O₆. HCl. H₂ O: C, 59.27; H, 6.10; N, 11.15.

Found: C, 59.03; H, 6.14; N, 10.89.

MS (EI) 573.

EXAMPLE 39 MethylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-[[4-(trifluoromethyl)phenyl]methyl]-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (0.450 g, 1.03 mmol) in DMF (4mL) is added K₂ CO₃ (0.800 g, 5.80 mmol). After stirring for 5 minutes4-trifluoromethylbenzyl bromide (0.270 g, 1.13 mmol) is added. Themixture is stirred for 16 hours to generate a red colored mixture. Afterdiluting with ethyl acetate and washing with water and brine thesolution is dried over MgSO₄. A viscous oil is obtained uponchromatography on silica gel (eluant 1% methanol in chloroform) andevaporation of the solvents in vacuo. This orange oil is dissolved inether and treated with ethereal HCl to afford a foamy solid uponevaporation in vacuo. This solid is dissolved in methylene chloride andtreated with pentane to afford a pale yellow solid.

Anal. Calcd. for C₃₃ H₃₅ N₄ O₄ F₃. HCl. 0.67 H₂ O: C, 59.57; H, 5.83; N,8.69.

Found: C, 59.55; H, 5.65; N, 8.39.

MS (EI) 596.

EXAMPLE 40 MethylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(3-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemono hydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate hydrochloride (0.50 g, 1.05 mmol) in DMF(4 mL) is added K₂ CO₃ (0.730 g, 5.29 mmol). After stirring for 5minutes. 3-thienylmethyl bromide (0.250 g, 1.41 mmol) is added. Themixture is stirred for 16 hours to generate a viscous pale brown coloredmixture. After diluting with ethyl acetate and washing with water andbrine the solution is dried over MgSO₄. A viscous oil is obtained uponchromatography on silica gel (eluant 0.5% methanol in chloroform) andevaporation of the solvents in vacuo. This oil is dissolved in ether andtreated with ethereal HCl to afford a foamy solid upon evaporation invacuo. This solid is crystallized from 2-propanol/ether.

Anal. Calcd. for C₃₃ H₃₅ N₄ O₄. HCl. 0.67 H₂ O: C, 60.99; H, 6.18; N,9.81.

Found: C, 60.83; H, 6.24; N, 9.61.

mp 178°-179° C.; MS (EI) 534.

EXAMPLE 41 MethylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(2-phenylethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemono hydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride (0.500 g, 1.05 mmol) in DMF (4 mL) is added K₂ CO₃(0.730 g, 5.29 mmol). After stirring for 5 minutes 2-phenylethyl bromide(0.215 mL, 1.57 mmol) is added. The mixture is stirred for 16 hours togenerate a viscous yellow colored mixture. After diluting with ethylacetate and ether and washing with water and brine the solution is driedover MgSO₄. A viscous oil is obtained upon chromatography on silica gel(eluant chloroform) and evaporation of the solvents in vacuo. This oilis dissolved in ether and treated with ethereal HCl to afford a foamysolid upon evaporation in vacuo. This solid is crystallized from2-propanol/ether.

Anal. Calcd. for C₃₃ H₃₅ N₄ O₄. HCl: C, 65.50; H, 6.78; N, 9.22.

Found: C, 65.68; H, 6.83; N, 9.58.

mp 150°-151° C.; MS (CI) 543 (M+1).

EXAMPLE 42 MethylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(diphenylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemono hydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoatehydrochloride (0.361 g, 0.76 mmol) in DMF (4 mL) is added K₂ CO₃ (0.525g, 3.80 mmol). After stirring for 5 minutes diphenylmethyl bromide(0.240 g, 0.97 mmol) is added. The mixture is stirred for 16 hours togenerate a viscous yellow colored mixture. After diluting with ether andwashing with water and brine the solution is dried over MgSO₄. This oilwas redissolved in DMF (4 mL) and K2CO₃ (0.525 g, 3.80 mmol) andbromodiphenyl methane (0.560 g, 2.27 mmol) is added. The mixture isstirred for 16 hours to generate a red colored mixture. After dilutingwith ether and washing with water and brine the solution is dried overMgSO₄. A viscous oil is obtained upon chromatography on silica gel(eluant chloroform) and evaporation of the solvents in vacuo. This oilis dissolved in ether and treated with ethereal HCl to afford a foamysolid upon evaporation in vacuo. This solid is crystallized from2-propanol/ether.

Anal. Calcd. for C₃₇ H₄₀ N₄ O₄. HCl: C, 69.31; H, 6.45; N, 8.74.

Found: C, 69.03; H, 6.09; N, 8.34.

mp 184°-185° C.; MS (EI) 604.

EXAMPLE 43 MethylZ-4-[[2-butyl-5-[[1-butyl-3-(cyclohexylmethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemono hydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate(0.250 g, 0.57 mmol) in DMF (4 mL) is added sodium hydride (80%dispersion in oil) (0.02 g, 0.67 mmol). After stirring for 5 minutescyclohexylmethyl bromide (0.20 mL, 1.43 mmol) is added. The mixture isstirred for 16 hours and then a further amount of cyclohexylmethylbromide is added (0.20 mL, 1.43 mmol) along with a catalytic amount ofsodium iodide. The mixture is stirred for 16 hours, diluted with ether,washed with water and brine and dried over MgSO₄. A viscous oil isobtained upon chromatography on silica gel (eluant 1.0% methanol inchloroform) and evaporation of the solvents invacuo. This oil isdissolved in ether and treated with ethereal HCl to afford a foamy solidupon evaporation in vacuo. This solid is crystallized from2-propanol/ether.

Anal. Calcd. for C₃₁ H₄₂ N₄ O₄. HCl: C, 65.19; H, 7.59; N, 9.81.

Found: C, 65.25; H, 7.64; N, 9.85.

mp 157°-158° C.; MS (EI) 534.

EXAMPLE 44 MethylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(1H-tetrazol-5-ylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl)methyl)benzoate(0.300 g, 0.68 mmol) in DMF (5 mL) is added K₂ CO₃ (0.500 g, 3.62 mmol).After stirring for 5 minutes 2-triphenylmethyl-1H-tetrazol-5-ylmethylchloride (0.500 g, 1.39 mmol) is added. The mixture is stirred for 16hours to generate a viscous orange colored mixture. After diluting withethyl acetate and washing with water and brine the solution is driedover MgSO₄. A viscous oil is obtained upon chromatography on silica gel(eluant 0.5% methanol in chloroform) and evaporation of the solvents invacuo. This oil is dissolved in methanol (50 mL) and treated with aceticacid (0.04 mL, 0.70 mmol). After heating at 90° C. (oil bath temp.) for2 hours the solution is cooled and treated with water (10 mL) andhexanes (100 mL). The aqueous organic layer is separated and evaporated.This solid is redissolved in ethyl acetate/methylene chloride and washedwith pH 7 buffer, dried over MgSO₄₄ and evaporated in vacuo. Thehydrochloride salt is then prepared by dissolving this solid in methanoland treating with ethereal HCl. Evaporation in vacuo of this solutionand crystallization (2-propanol/ether) affords the required compound.

Anal. Calcd. for C₂₆ H₃₂ N₈ O₄. HCl: C, 56.38; H, 6.00; N, 19.73.

Found: C, 56.06; H, 5.97; N, 20.12

mp 192°-195° C.; MS (CI) 521

EXAMPLE 45 MethylZ-4-[[2-butyl-5-[[1-butyl-3-(1H-imidazol-5-ylmethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate hydrochloride (0.237 g, 0.50mmol) in DMF (3 mL) is added K₂ CO₃ (0.350 g, 2.54 mmol). After stirringfor 5 minutes 4-(chloromethyl)-1-(triphenylmethyl)-1H-imidazole (0.250g, 0.70 mmol) is added. The mixture is stirred for 16 hours, dilutedwith ethyl acetate, washed with water and brine and then dried overMgSO₄. A viscous oil is obtained upon chromatography on silica gel(eluant 0.5% methanol in chloroform) and evaporation of the solvents invacuo. This oil is dissolved in methanol (80 mL) and treated with aceticacid (30 mL). After heating at 90° C. (oil bath temp.) for 4 hours thesolution is cooled and treated with water (10 mL) and hexanes (100 mL).The aqueous organic layer is separated and evaporated. This solid isredissolved in ethyl acetate/methylene chloride and washed with pH 7buffer, dried over MgSO₄₄ and evaporated in vacuo. The hydrochloridesalt is then prepared by dissolving this solid in methanol and treatingwith ethereal HCl. Evaporation in vacuo of this solution andcrystallization (2-propanol/ether) affords the required compound.

Anal. Calcd. for C₂₈ H₃₄ N₆ O₄. 2HCl. H₂ O: C, 55.17; H, 6.28; N, 13.79.

Found: C, 54.88; H, 6.13; N, 13.24.

mp 202°-205° C.; MS (EI) 518.

EXAMPLE 46 Diethyl 1-hexyl-2,5-dioxo-4-imidazolylphosphonate

To a solution of diethyl 2,5-dioxo-4-imidazolylphosphonate (6.00 g,0.025 moles) in DMF (15 mL), under N₂, is added K₂ CO₃ (17.5 g, 0.127moles) and 1-iodohexane (3.75 mL, 0.025 moles). This mixture is stirredat room temperature for 16 hours. The mixture is diluted with ether (300mL) and washed with water and brine and then dried over MgSO₄.Evaporation of solvents under high vacuum affords the required productas a viscous yellow oil. (Mass spectrometry also revealed a small amountof diethyl 1,3-dihexyl-2,5-dioxo-4-imidazolylphosphonate).

MS (EI) 321.

EXAMPLE 47 MethylZ-4-[[2-butyl-5-[(1-hexyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate

To a solution of diethyl 1-hexyl-2,5-dioxo-4-imidazolylphosphonate (3.50g, 0.011 moles) in methylene chloride (30 mL) at -40° C. is added1,8-diazabicyclo [5.4.0]undec-7-ene (1.64 mL, 0.011 moles). The yellowsolution is stirred for 5 minutes and then a solution of methyl4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoate (3.25 g, 0.011moles) is added. This mixture is allowed to stir for 16 hours withwarming to room temperature. The mixture is diluted with ethyl acetateand washed with water and then brine. After adding methylene chloride(50 mL) and drying over MgSO₄₄ the product is isolated as a yellow solidby concentration in vacuo and treatment with ether.

Anal. Calcd. for C₂₆ H₃₄ N₄ O₄. 0.3 H₂ O: C, 66.16; H, 7.39; N, 11.87.

Found: C, 65.96; H, 7.07; N, 11.70.

mp 178°-180° C.; MS (EI) 466.

EXAMPLE 48 MethylZ-4-[[2-butyl-5-[(3-butyl-1-hexyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[1-hexyl-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.50 g, 1.07 mmol) in DMF (4 mL) is added K₂ CO₃ (0.740 g, 5.36 mmol).After stirring for 5 minutes 1-iodobutane (0.158 mL, 1.39 mmol) isadded. The mixture is stirred for 16 hours. After diluting with ether(150 mL) and washing with water and brine the solution is dried overMgSO₄. A viscous oil is obtained by evaporation of the solvents invacuo. This yellow oil is dissolved in ether and treated with etherealHCl to precipitate a gummy solid. This gum is crystallized form2-propanol/ether.

Anal. Calcd. for C₃₀ H₄₃ N₄ O₄. HCl 0.3 H₂ O: C, 63.64; H, 7.95; N,9.89.

Found: C, 63.65; H, 7.56; N, 9.43.

mp 144°-145° C.; MS (EI) 522.

EXAMPLE 49 MethylZ-4-[[2-butyl-5-[[1-hexyl-2,5-dioxo-3-(3-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-hexyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate(0.515 g, 1.11 mmol) in DMF (7 mL) is added K₂ CO₃ (0.760 g, 5.51 mmol).After stirring for 5 minutes 3-thienylmethyl bromide (0.39 g, 2.20 mmol)is added. The mixture is stirred for 16 hours to generate a viscous palebrown colored mixture. After diluting with ether and washing with waterand brine the solution is dried over MgSO₄. The solvents are evaporatedin vacuo and this oil is dissolved in ether and treated with etherealHCl to afford a foamy solid upon evaporation in vacuo. This solid iscrystallized from 2-propanol/ether.

Anal. Calcd. for C₃₁ H₃₈ N₄ O₄ S. HCl. H₂ O: C, 60.32; H, 6.70; N, 9.08.

Found: C, 59.95; H, 6.55; N, 8.68.

MS (FAB) 564.

EXAMPLE 50 MethylZ-4-[[2-butyl-5-[[1-hexyl-2,5-dioxo-3-(phenylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-hexyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate(0.516 g, 1.11 mmol) in DMF (7 mL) is added K₂ CO₃ (0.760 g, 5.51 mmol).After stirring for 5 minutes benzylbromide (0.150 mL, 1.26 mmol) isadded. The mixture is stirred for 16 hours. After diluting with etherand ethyl acetate and washing with water and brine the solution is driedover MgSO₄. A viscous oil is obtained upon evaporation of the solventsin vacuo. This yellow oil is dissolved in ether and treated withethereal HCl to afford a foamy solid upon evaporation in vacuo. Thissolid is crystallized from 2-propanol/ether.

Anal. Calcd. for C₃₃ H₄₀ N₄ O₄. HCl: C, 64.68; H, 7.42; N, 10.06.

Found: C, 64.76; H, 7.06; N, 10.53.

mp 98°-100° C.; MS (CI) 557 (M+1).

EXAMPLE 51 MethylZ-4-[[2-butyl-5-[1-hexyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatedihydrochloride

To a solution of methylZ-4-[[2-butyl-5[(1-hexyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate0.300 g, 0.643 mmol) in DMF (4 mL) is added K₂ CO₃ (0.440 g, 3.19 mmol).After stirring for 5 minutes 4-chloromethyl-2-methylthiazolehydrochloride (0.237 g, 1.29 mmol) is added. The mixture is stirred for16 hours in which time a pale brown slurry forms. After diluting withethyl acetate and washing with water and brine the solution is driedover MgSO₄. Chromatography eluting with 2% methanol in chloroform andevaporation in vacuo affords a viscous oil. This oil is dissolved inether and treated with ethereal HCl to afford a foamy solid uponevaporation in vacuo. This solid is crystallized from 2-propanol/ether.

Anal. Calcd. for C₃₁ H₃₉ N₅ O₄ S. 2HCl. H₂ O: C, 55.67; H, 6.48; N,10.47.

Found: C, 55.57; H, 6.29; N, 10.15.

mp 160°-162° C.; MS (EI) 577.

Example 52 Diethyl 1-(methoxymethyl)-2,5-dioxo-4-imidazolylphosphonate

To a solution of diethyl 2,5-dioxo-4-imidazolylphosphonate (3.61 g,0.015 moles) in DMF (10 mL), under N₂, is added sodium hydride (80%dispersion in oil) (0.55 g, 0.018 moles) and stirred for 5 minutes.Chloromethyl methyl ether (tech. grade 85%) (1.9 mL, 0.021 moles) isadded. This mixture is stirred at room temperature for 4 hours, dilutedwith ether and ethyl acetate (300 mL) and then washed with water andbrine before drying over MgSO₄. The aqueous layer is back extracted withmethylene chloride and combined with the previous organic fraction.Evaporation of solvents and chromatography (eluant 1% methanol inchloroform) and evaporation under high vacuum affords the requiredproduct.

MS (EI) 280.

EXAMPLE 53 MethylZ-4-[[2-butyl-5-[[(1-(methoxymethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate

To a solution of diethyl1-(methoxymethyl)-2,5-dioxo-4-imidazolylphosphonate (2.40 g, 8.57 mmol)in methylene chloride (10 mL) at 0° C. is added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.30 mL, 8.71 mmol). The yellow solution is stirredfor 5 minutes and then a solution of methyl4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoate (2.0 g, 6.67mmol)is added. This mixture is allowed to stir for 16 hours, dilutedwith ethyl acetate, and washed with water and then brine. After addingmethylene chloride (50 mL) and drying over MgSO₄₄ the product isisolated as a yellow solid by partial concentration in vacuo andtreatment with ether.

Anal. Calcd. for C₂₂ H₂₆ N₄ O₅ : C, 61.96; H, 6.15; N, 13.14.

Found: C, 61.69; H, 6.17; N, 12.99.

mp 185°-186° C.; MS (EI) 426.

EXAMPLE 54 MethylZ-4-[[2-butyl-5-[[3-butyl-1-(methoxymethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[1-(methoxymethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.70 g, 1.07 mmol) in DMF (4 mL) is added K₂ CO₃ (1.13 g, 8.19 mmol).After stirring for 5 minutes 1-iodobutane (0.24 mL, 2.11 mmol) is added.The mixture is stirred for 16 hours. After diluting with ether (150 mL)and washing with water and brine the solution is dried over MgSO₄. Aviscous oil is obtained by evaporation of the solvents in vacuo. Thisyellow oil is dissolved in ether and treated with ethereal HCl toprecipitate a gummy solid. This gum is crystallized from2-propanol/ether.

Anal. Calcd. for C₂₆ H₃₄ N₄ O₅. HCl: C, 60.17; H, 6.80; N, 10.79.

Found: C, 59.87; H, 6.88; N, 10.73.

mp 133°-134° C.; MS (EI) 482.

EXAMPLE 55 MethylZ-4-[[2-butyl-5-[[1-(methoxymethyl)-2,5-dioxo-3-(phenylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[1-methoxymethyl-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.34 g, 0.79 mmol) in DMF (4 mL) is added K₂ CO₃ (0.55 g, 3.99 mmol).After stirring for 5 minutes benzylbromide (0.113 mL, 0.95 mmol) isadded. The mixture is stirred for 16 hours, diluted with ether an washedwith water and brine and then dried over MgSO₄. A viscous oil isobtained upon evaporation of the solvents in vacuo. This yellow oil isdissolved in ether and treated with ethereal HCl to afford a foamy solidupon evaporation in vacuo. This solid is crystallized from2-propanol/ether.

Anal. Calcd. for C₂₉ H₃₂ N₄ O₅. HCl: C, 62.98; H, 6.01; N, 10.13.

Found: C, 62.59; H, 5.97; N, 9.92.

mp 137°-138° C.; MS (EI) 516.

EXAMPLE 56 MethylZ-4-[[2-butyl-5-[[1-(methoxymethyl)-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatedihydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[1-(methoxymethyl)-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (0.307 g, 0.721 mmol) in DMF (4mL) is added K₂ CO₃ (0.500 g, 3.62 mmol). After stirring for 5 minutes4-chloromethyl-2-methylthiazole hydrochloride (0.265 g, 1.44 mmol) isadded. The mixture is stirred for 48 hours. A pale brown slurry resultswhich was diluted with ethyl acetate and washed with water and brine andthen dried over MgSO₄. Chromatography eluting with 1-% methanol inchloroform and evaporation in vacuo affords a viscous oil. This oil isdissolved in ether and treated with ethereal HCl to afford a foamy solidupon evaporation in vacuo. This solid is crystallized from2-propanol/ether.

Anal. Calcd. for C₂₇ H₃₁ N₅ O₅ S. 2HCl: C, 53.11; H, 5.45; N, 11.47.

Found: C, 53.07; H, 5.46; N, 11.48.

mp 205°-209° C.; MS (EI) 537.

EXAMPLE 57 MethylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-[(2-pyridinyl-N-oxide)methyl]-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate(0.569 g, 1.2 mmol) in DMF (5 mL) is added K₂ CO₃ (2.00 g, 15 mmol).After stirring for 5 minutes 2-chloromethylpyridine-N-oxide (0.230 g,1.3 mmol) is added and the mixture is stirred for 16 hours. The darkbrown mixture is filtered, concentrated in vacuo, and dissolved in 30%methylene chloride in ether (50 mL). This solution is washed with waterand dried over K₂ CO₃ and charcoal. A viscous oil is obtained byevaporation of the solvents in vacuo. This yellow oil is dissolved inhot ethyl acetate (5 mL) and upon brief standing crystallization occurs.The crystals are collected and washed with ether.

Anal. Calcd. for C₃₀ H₃₅ N₅ O₅.: C, 66.04; H, 6.47; N, 12.84.

Found: C, 66.34; H, 6.56; N, 12.88.

mp 150°-152° C.; MS (CI) 546 (M+1).

EXAMPLE 58 MethylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(2-pyridinylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatedihydrochloride

A solution of methylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-[(2-pyridinyl-N-oxide)methyl]-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatein methylene chloride (2 mL) is added dropwise over 3 minutes tophosphorus trichloride (2.0 mL). After 15 minutes the mixture isconcentrated under reduced pressure. The residue is dissolved in warmiso-propanol (3 mL) and saturated with HCl gas briefly. Ether is addedand the crystals collected and washed with ether. A portion of thissample is recrystallized from 2-propanol/ether.

Anal. Calcd. for C₃₀ H₃₅ N₅ O₄. 2HCl. 0.5 H₂ O: C, 58.91; H, 6.26; N,11.45.

Found: C, 58.65; H, 6.04; N, 11.15.

mp 195°-197° C.; MS (CI) 530 (M+1).

EXAMPLE 59Z-4-[[2-butyl-5-[[1-butyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid

A mixture of methylZ-4-[[2-butyl-5-[[1-butyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.428 g, 0.65 mmol) and 2N HCl (12 mL) is refluxed for 1 hour in whichtime all the solid dissolved. Solvents are removed in vacuo and themixture is evaporated from ethanol (5 mL) three times. The solid thatresults is treated with 5% aqueous sodium acetate (10 mL) and water (10mL) to precipitate a gummy solid which is dissolved in methylenechloride (30 mL). The organic layer is dried over Na₂ SO₄ and thenevaporated in vacuo. The residue is recrystallized from hot ethylacetate/hexane.

Anal. Calcd. for C₂₈ H₃₃ N₅ O₄ S: C, 62.78.; H, 6.21; N, 13.07.

Found: C, 63.01; H, 6.27; N, 13.05.

mp 152°-154° C.; MS (CI) 536 (M+1).

EXAMPLE 60 Isomerisation ofZ-4-[[2-butyl-5-[[1-butyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid to E-4-[[2-butyl-5-[[1-butyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid

MethylZ-4-[[2-butyl-5-[[1-butyl-3-[[4-methyl-2-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoic acid(0.25 g, 0.46 mmol) was dissolved in concentrated HCl (15 mL) and themixture is refluxed for 4 hours. The mixture is concentrated in vacuoand aquous sodium acetate is added. The precipitate is collected andwashed with water. This solid is dissolved in methanol (2 mL) andtreated with charcoal and then filtered and concentrated in vacuo. Theresidue was recrystallized from hot ethyl acetate.

Anal. Calcd. for C₂₈ H₃₃ N₅ O₄ S. 0.25 H₂ O: C, 62.26; H, 6.25; N,12.97.

Found: C, 62.28; H, 6.16; N, 12. 62.

mp 181°-183° C.; MS (CI) 536 (M+1).

EXAMPLE 61 Methyl Z-4-[[2-butyl-5-[[1-butyl-3-[(2-chlorophenyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate(0.474 g, 1.0 mmol) in DMF (10 mL) is added K₂ CO₃ (2.0 g, 15 mmol).After stirring for 5 minutes 1-chloro-2-chloromethylbenzene (0.177 g,1.1 mmol) is added and the mixture is stirred for 16 hours. The mixtureis filtered, concentrated in vacuo, and then dissolved in ether (50 mL).This solution is washed with water and dried over K₂ CO₃. A viscous oilis obtained by evaporation of the solvents in vacuo which is purifiedvia chromatography, eluant 1% methanol in chloroform. The appropriatefraction is dissolved in ether and treated with ethereal HCl and thenevaporate din vacuo to afford a solid foam.

Anal. Calcd. for C₃₁ H₃₅ ClN₄ O₄.HCl. 0.5 H₂ O: C, 61.18; H, 6.13; N,9.21.

Found: C, 60.85; H, 6.18; N, 9.07.

mp 120°-130° C.; MS (CI) 563 (M+1).

EXAMPLE 62 MethylZ-4-[[2-butyl-5-[[1-butyl-3-[(2-amino-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatedihydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (0.569 g, 1.2 mmol) in DMF (5mL) is added K₂ CO₃ (2.0 g, 15 mmol). After stirring for 5 minutes2-amino-4-chloromethylthiazole hydrochloride (0.222 g, 1.2 mmol) isadded. The mixture is stirred for 48 hours and the filtered. Thefiltrate is concentrated in vacuo and dissolved in methylene chloride(30 mL). This solution is washed with water and drived over K₂ CO₃ andcharcoal. A viscous oil is obtained by evaporation of the solvents invacuo. This oil is dissolved in ether and treated with ethereal HCl toprecipitate a gum which is collected by decantation. This gum isrecrystallized from 2-propanol/ether.

Anal. Calcd. for C₂₈ H₃₄ N₆ O₄ S. 2HCl. 2H₂ O: C, 50.90; H, 6.10; N,12.87.

Found: C, 51.23; H, 6.10; N, 12.67.

mp 171°-174° C.; MS (CI) 551 (M+1).

EXAMPLE 63 MethylZ-4-[[2-butyl-5-[2,5-dioxo-3-[(2-thienyl)methyl]-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate

HCl gas is passed through a mixture of the Z and E isomers of4-[[2-butyl-5-[2,5-dioxo-3-[(2-thienyl)methyl]-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid (3.50 g, 7.5 mmol) in methanol (250 mL). The solid dissolved andthe internal temperature rises to 50° C. The solution is allowed to stirfor about 16 hours at room temperature. The solution is concentrated toapproximately 10 mL volume and saturated NaHCO₃ (150 mL) is added toadjust the pH to 7.5. The mixture is filtered and washed with water. TheZ and E isomers are separated by chromatography (eluant 1-5% methanol inchloroform) and crytallized from warm ethyl acetate.

Anal. Calcd. for C₂₅ H₂₆ N₄ O₄ S. 0.1 H₂ O: C, 61.89; H, 5.44; N, 11.55.

Found: C, 62.07; H, 5.34; N, 11.31.

mp 167°-169° C.; MS (CI) 479 (M+1).

EXAMPLE 64 MethylZ-4-[[2-butyl-5-[[3-[(4-chlorophenyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

HCl gas is passed through a solution of methylZ-4-[[2-butyl-5-[[3-[(4-chlorophenyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid (0.73 g, 1.5 mmol) in methanol (15 mL). The solution is allowed tostire for 16 hours at room temperature. The solution is concentrated toapproximately 5 mL volume and then ether is added to inducecrystallization. The mixture is filtered and washed with ether.

Anal. Calcd. for C₂₇ H₂₇ N₄ O₄ Cl. HCl: C, 59.67; H, 5.19; N, 10.31.

Found: C, 59.45; H, 5.09; N, 9.99.

mp 240°-242° C.; MS (CI) 507.

EXAMPLE 65 4-[[2-Butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinyl)methyl]-1H-imidazol-1-yl]methyl]benzoic acid

To a solution of E4-[[2-Butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinyl)methyl]-1H-imidazol-1-yl]methyl]benzoic acid (0.84 g, 2.00 mmol) in 1NNaOH (2.04 mL, 2.04 mmol) and water (500 mL) is added PtO₂ (0.200 g) andthen a hydrogen balloon is attached. The mixture is stirred for 3 hours.1N HCl (2.04 mL, 2.04 mmol) is added and then the mixture isconcentrated at reduced pressure. Ethanol (50 mL) is added and themixture filtered. After evaporating in vacuo the residue is purified bycrystallization and chromatography.

Anal. Calcd. for C₂₃ H₃₀ N₄ O₄ S. H₂ O: C, 62.14; H, 7.26; N, 12.61.

Found: C, 62.35; H, 7.08; N, 12.68.

MS (CI) 427 (M+1).

EXAMPLE 66 MetylZ-4-[[2-butyl-5-[[1-butyl-3-[(4-chlorophenyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[1-butyl-3-[(4-chlorophenyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.50 g, 0.92 mmol) in DMF (5 mL) is added K₂ CO₃ (2.0 g, 15 mmol).After stirring for 5 minutes 1-iodobutane (0.184 g, 1.0 mmol) is added.The mixture is stirred for 4 hours. The mixture is filtered and thefiltrate s concentrated in vacuo and treated with water (20 mL) toafford a gum upon decantation. This gum is dissolved in ether and washedwith water and then drived over K₂ CO₃. A viscous oil is obtained byevaporation of the solvents in vacuo. This oil is dissolved in ether andtreated with ethereal HCl to precipitate a gum which is collected bydecantation. This gum solidifies upon extended evaporation in vacuo.This solid foam contains 2-propanol as determined by 1H-NMR

Anal. Calcd. for C₃₁ H₃₅ ClN₄ O₃ S.HCl.H₂ O. 0.15 i-PrOH: Calcd. C,60.26; H, 6.31; N, 8.95. Found: C, 60.50; H, 6.12; N, 8.86.

MS (CI) 564 (M+1).

EXAMPLE 67 MethylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.70 g, 1.46 mmol) in warm DMF (10 mL) is added K₂ CO₃ (2.0 g, 15mmol). After stirring for 5 minutes 1-iodobutane (0.312 g, 1.7 mmol) isadded. The mixture is stirred for 2 hours. The mixture is filtered andthe filtrate is concentrated in vacuo and treated with water (20 mL) toafford a gum upon decantation. This gum is dissolved in ether and washedwith water and then dried over K₂ CO₃. A viscous oil is obtained byevaporation of the solvents in vacuo. This oil is dissolved in ether andtreated with ethereal HCl to precipitate a gum which is collected bydecantation. This gum is dissolved in warm ethanol and ether is added toinduce crystallization. The crystals are collected and washed withether.

Anal. Calcd. for C₂₉ H₃₄ N₄ O₄ S.HCl: C, 60.99; H, 6.18; N, 8.95. N,9.81.

Found: C, 60.69; H, 6.16; N, 9.69.

mp 185°-187° C.; MS (CI) 535 (M+1).

EXAMPLE 68 MethylZ-4-[[2-butyl-5-[[1-butyl-3-[2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatedihydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[1-butyl-3-[2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatehydrochloride (0.474 g, 1.0 mmol) in DMF (5 mL) is added K₂ CO₃ (2.0 g,15 mmol). After stirrng for 5 minutes 2-methyl-4-(chloromethyl)thiazolehydrochloride (0.184 g, 1.0 mmol) is added. An additional amount of DMF(10 mL) is added after stirring for 30 minutes. The mixture is stirredfor 5 days and then filtered. the filtrate is concentrated in vacuo anddissolved in ether (50 mL). This solution is washed with water anddrived over K₂ CO₃ and charcoal. A viscous oil is obtained byevaporation of the solvents in vacuo which is dissolved in ether andtreated with ethereal HCl and then evaporated in vacuo to afford a solidfoam. Recrystallized from 2-propanol/ether.

Anal. Calcd. for C₂₉ H₃₅ N₅ O₄ S.2HCl.0.5 H₂ O: C, 55.14; H, 6.07; N,11.08.

Found: C, 55.00; H, 6.20; N, 11.09.

mp 124°-127° C.; MS (CI) 550 (M+1).

EXAMPLE 69 MethylZ-4-[[2-butyl-5-[[1-butyl-3-[(3,5-dimethyl-4-isoxazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[1-butyl-3-[(3,5-dimethyl-4-isoxazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(1.00 g, 2.281 mmol) in DMF (10 mL) is added K₂ CO₃ (1.580 g, 0.011moles). After stirring for 15 minutes4-chloromethyl-3,5-dimethylisoxazole (0.35 g, 2.39 mmol) is added. Themixture is stirred for 24 hours. The solvents were removed under highvacuum. After diluting with ethyl acetate and washing with water andbrine the solution is dried over MgSO₄. Evaporation in vacuo affords aviscous oil which is dissolved in ether and treated with ethereal HCl toafford a foamy solid upon evaporation in vacuo. This solid iscrystallized from ethyl acetate/hexane.

Anal. Calcd. for C₃₀ H₃₇ N₅ O₅.HCl: C, 61.69; H, 6.56; N, 11.99.

Found: C, 61.40; H, 6.58; N, 11.86.

mp 146°-148° C.; MS (CI) 548 (M+1).

EXAMPLE 70 MethylZ-4-[[2-butyl-5-[[1-butyl-3-(2-naphthalenylmethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[1-butyl-3-(2-naphthalenylmethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(1.00 g, 2.281 mmol) in DMF (10 mL) is added K₂ CO₃ (1.580 g, 0.011moles). After stirring for 15 minutes 1-bomomethylnaphthalene (0.53 g,2.40 mmol) is added. The mixture is stirred for 24 hours then thesolvents were removed under high vacuum. After diluting with ethylacetate and washing with water and brine the solution is dried overMgSO₄. Evaporation in vacuo affords a viscous oil which is dissolved inether and treated with ethereal HCl to afford a foamy solid uponevaporation in vacuo. This solid is crystallized from ethylacetate/ether.

Anal. Calcd. for C₃₅ H₃₈ N₄ O₄.HCl.2H₂ O: C, 64.55; H, 6.66; N, 8.60.

Found: C, 64.74; H, 6.51; N, 8.47.

mp 93°-95° C.; MS (CI) 579 (M+1).

EXAMPLES 71a AND 71b 71aZ-N-[4-[[2-butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]phenyl]-1,1,1-trifluoromethanesulfonamide

To a solution of diethyl 3-butyl-2,5-dioxo-4-imidazolylphosphonate (1.48g, 5.06 mmol) in ethanol (10 mL) was cautiously added sodium hydridebatchwise (1.0 g, 25 mmol). the cloudy solution was stirred for 30 min.the aldehyde 1,1-dimethylethyl4-[(2-butyl-5-formyl-1H-imidazol-1-yl]methyl]benzoate (0.68 g, 1.75mmol) in ethanol (10 mL) was added over 30 min. This solution was heatedat reflux for 2 hours. The reactin was cooled to room temperature andtreated with glacial acetic acid (2 mL). Evaporation in vacuo affords athick gel. Chromatography eluting with 0-4% methanol in chloroformaffords the required Z-isomer

Anal. Calcd. for C₂₃ H₂₈ N₅ O₄.0.25H₂ O: C, 51.92; H, 5.40; N, 13.16.

Found: C, 51.99; H, 5.62; N, 12.85.

mp 171°-5° C.; MS (CI) 528 (M+1).

and then the more polar E-isomer

71bE-N-[4-[[2-butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]phenyl]-1,1,1-trifluoromethanesulfonamide

Anal. Calcd. for C₂₃ H₂₈ N₅ O₄.0.25H₂ O.: C, 51.92; H, 5.40; N, 13.16.

Found: C, 51.92; H, 5.41; N, 13.50.

mp 177°-178° C.; MS (CI) 528 (M+1).

EXAMPLE 72 MethylZ-4-[[2-butyl-5-[[1-butyl-3-[(3-methyl-2-thienyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatehydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[1-butyl-3-[(3-methyl-2-thienyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(1.0 g, 2.876 mmol) in dry THF (20 mL) was carefully added sodiumhydride (0.14 g, 4.67 mmol) and then the mixture was allowed to stir for20 minutes. 2-Bromomethyl-3-methyl-thiophene (0.75 g, 3.925 mmol) in THF(10 mL) was added dropwise over 10 minutes. After stirring for 2 hoursdilute aqueous HCl was added to the orange brown mixture until the pHwas 7. This mixture was extracted with ethyl acetate and then dried overMgSO₄. The product was isolated by chromatography eluting with acetonein methylene chloride. The hydrochloride salt was prepared by theaddition of HCl in isopropanol, and then crystallisation from THF/ether.

Anal. Calcd. for C₃₀ H₃₆ N₄ O₄ S. 1.14HCl: C, 61.05; H, 6.34; N, 9.49.

Found: C, 60.67; H, 6.05; N, 9.27.

mp 160°-162° C.; MS (CI) 549 (M+1).

EXAMPLE 73Z-4-[[2-butyl-5-[(1,3-dibutyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoicacid

1,1-dimethylethylZ-4-[[2-butyl-5-[(1,3-dibutyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate(0.88 g, 1.64 mmol) was disolved in methylene chloride (16 mL) andtrifluoroacetic acid (16 mL). After stirring for 3 hours the reactionmixture was evaporated in vacuo. Dilute NaHCO₃ was added to adjust thepH to 6 and extracted with ethyl acetate. This extract was dried overMgSO₄ and then evaporated in vacuo and purified via chromatograph(eluant methanol in chloroform).

Anal. Calcd. for C₂₇ H₃₆ N₄ O₄ : C, 67.48; H, 7.55; N, 11.66.

Found: C, 67.48; H, 7.76; N, 11.48.

mp 182°-184° C.; MS (CI) 481 (M+1).

EXAMPLE 74Z-4-[[2-butyl-5-[[1-butyl-3-[(5-methyl-2-thienyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid

1,1-dimethylethylZ-4-[[2-butyl-5-[[1-butyl-3-[(5-methyl-2-thienyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.56 g, 0.948 mmol) was disolved in methylene chloride (10 mL) andtrifluoroacetic acid (5 mL). After stirring for 16 hours the reactionmixture was evaporated in vacuo. pH 7 buffer was added and the mixtureextracted with ethyl acetate. This extract was dried over MgSO₄ and thenevaporated in vacuo and crystallized from THF/ether.

Anal. Calcd. for C₂₉ H₃₄ N₄ O₄ S.0.3H₂ O: C, 65.15; H, 6.41; N, 10.48.

Found: C, 64.46; H, 6.62; N, 10.39.

mp 163°-165° C.; MS (CI) 535 (M+1).

EXAMPLE 75Z-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid

1,1-dimethylethylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]-benzoate(1.28 g, 2.26 mmol) was disolved in methylene chloride (25 mL) andtrifluoroacetic acid (3.3 mL). After stirring for 16 hours an additionalamount of trifluoroacetic acid (3 mL) was added. Stirred for a further 6hours and then the reaction mixture was evaporated in vacuo. pH 7 bufferwas added and the mixture extracted with ethyl acetate. This extract wasdrived over MgSO₄ and then evaporated in vacuo and crystallized fromethyl acetate/ether.

Anal. Calcd. for C₂₈ H₃₂ N₄ O₄ S.0.5H₂ O: C, 63.50; H, 6.28; N, 10.58.

Found: C, 63.58; H, 6.16; N, 10.44.

mp 167°-170° C.; MS (CI) 521 (M+1).

EXAMPLES 76a AND 76b 76aZ-1-Butyl-5-[[2-butyl-3-[[4-(1H-tetrazol-5-yl)phenyl]methyl]-3H-imidazol-4-yl]methylene]-2,4-imidazolidinedione

To a solution of diethyl 3-butyl-2,5-dioxo-4-imidazolyphosphonate (0.240g, 0.86 mmol) in ethanol (10 mL) was added sodium hydride (0.072 g, 1.80mmol) and the mixture sitted for 15 minutes. The aldehyde2-butyl-1-[4-[1-(triphenylmethyl)tetrazol-5-yl]phenyl]methyl]-5-formylimidazole(0.400 g, 0.72 mmol) was added along with methylene chloride (5 mL). Themixture was stirred for 16 hours. The solvets were removed in vacuoo andthe Z-isomer and E-isomer purified by chromatography eluting with 20%ethyl acetate in methylene chloride. The Z-isomer and the E-isomer wereeach separately dissolved in methanol (5 mL) containing a 10% aqueoussolution of citric acid (0.5 mL). The reaction mixture was refluxedovernight. Water (20 mL) was added and extracted with hexane. Themixture was then extracted with ethyl acetate and washed with brine anddried over MgSO₄. After evaporating in vacuo the residue wascrystallized from a combination of hexane, ethyl acetate and methanol.

Anal. Calcd. for C₂₃ H₂₈ N₈ O₂ S.0.9H₂ O: C, 59.40; H, 6.47; N, 24.09.

Found: C, 59.79; H, 6.18; N, 23.57.

mp 140°-142° C.; MS (CI) 449 (M+1).

76bE-1-Butyl-5-[[2-butyl-3-[[4-(1H-tetrazol-5-yl)phenyl]methyl]-3H-imidazol-4-yl]methylene]-2,4-imidazolidinedione

Anal. Calcd. for C₂₃ H₂₈ N₈ O₂ S.1.67H₂ O: C, 57.72; H, 6.60; N, 23.41.

Found: C, 57.35; H, 5.94; N, 23.13.

MS (CI) 449 (M+1).

EXAMPLE 77 MethylZ-4-[[5-[[3-[(5-bromo-2-thienyl)methyl]-1-butyl-2,5-dioxo-4-imidazolidinylidene]methyl]-2-butyl-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate(0.750 g, 1.7 mmol) in DMF (10 mL) was added K₂ CO₃ (1.17 g, 0.0085moles). 2-bromomethyl-5-bromothiphene (0.46 g, 0.0018 moles) was addedin one portion and the mixture sitted for 16 hours. The reaction mixturewas filtered and evaporated in vacuo. The residue was extracted intoethyl acetate and then washed with water and brine. After drying overMgSO₄ and evaporation in vacuo the residue was purified bychromatography eluting with 10% ethyl acetate in methylene chloride. Therequired product was recrystallized as its hydrochloride salt.

Anal. Calcd. for C₂₉ H₃₃ N₄ O₄ BrS.HCl.0.72H₂ O: C, 52.54; H, 5.39; N,8.45.

Found: C, 52.54; H, 5.51; N, 8.42.

MS (CI) 613/615 (M+1).

EXAMPLE 78 MethylZ-4-[[5-[[3-[(4-bromo-2-thienyl)methyl]-1-butyl-2,5-dioxo-4-imidazolidinylidene]methyl]-2-butyl-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate(0.750 g, 1.7 mmol) in DMF (10 mL) was added K₂ CO₃ (1.17 g, 0.0085moles). 2-bromomethyl-4-bromothiophene (0.46 g, 0.0018 moles) was addedin one portion and the mixture stirred for 16 hours. The reactionmixture was filtered and evaporated in vacuo. The residue was extractedinto ethyl acetate and then washed with water and brine. After dryingover MgSO₄ and evaporation in vacuo the residue was dissolved in etherand treated with ethereal HCl to afford a white solid upon removal ofsolvents in vacuo.

Anal. Calcd. for C₂₉ H₃₃ N₄ O₄ BrS.HCl.1.22H₂ O: C, 51.83; H, 5.47; N,8.34.

Found: C, 51.82; H, 5.32; N, 8.18.

MS (CI) 613/615 (M+1).

EXAMPLE 79 Methyl Z-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-[2-(2-thienyl)ethyl]-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methyl Z-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-[2-(2-thienyl)ethyl]-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.750 g, 1.7 mmol) in DMF (20 mL) was added K₂ CO₃ (1.17 g, 0.0085moles). 2-(2-thienyl)ethyl bromide (0.35 g, 0.0018 moles) was added inone portion and the mixture stirred for 16 hours. The reaction mixturewas filtered and evaporated in vacuo. The residue was extracted intoethyl acetate and then washed with water and brine. After drying overMgSO₄ and evaporation in vacuo the residue was purified bychromatography eluting with 50% ethyl acetate in methylene chloride. Therequired product was dissolved in ether and treated with ethereal HCl toafford a white solid upon removal of solvents in vacuo.

Anal. Calcd. for C₃₀ H₃₇ N₄ O₄ S.HCl.1.15H₂ O: C, 59.47; H, 6.54; N,9.25.

Found: C, 59.48; H, 6.48; N, 9.01.

MS (CI) 549 (M+1).

EXAMPLE 80 Methyl Z-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-[2-(3-thienyl)ethyl]-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methyl Z-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-[2-(3-thienyl)ethyl]-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.750 g, 1.7 mmol) in DMF (20 mL) was added K₂ CO₃ (1.17 g, 0.0085moles). 2-(3-thienyl)ethyl bromide (0.35 g, 0.0018 moles) was added inone portion and the mixture stirred for 16 hours. A further amount of2-(3-thienyl)ethyl bromide (0.35 g, 0.0018 moles) was added and themixture stirred for 16 hours. The reaction mixture was filtered andevaporated in vacuo. The residue was extracted into ethyl acetate andthen washed with water and brine. After drying over MgSO₄ andevaporation in vacuo the residue was purified by chromatography elutingwith 20% ethyl acetate in methylene chloride. The required product wasdissolved in ether and treated with ethereal HCl to afford a white solidupon removal of solvents in vacuo.

Anal. Calcd. for C₃₀ H₃₇ N₄ O₄ S.HCl.0.87H₂ O: C, 59.97; H, 6.50; N,9.32.

Found: C, 59.99; H, 6.40; N, 9.27.

MS (CI) 549 (M+1).

EXAMPLE 81 MethylZ-4-[[5-[[3-[(5-bromo-3-thienyl)methyl]-1-butyl-2,5-dioxo-4-imidazolidinylidene]methyl]-2-butyl-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate(0.500 g, 1.1 mmol) in DMF (20 mL) was added K₂ CO₃ (0.76 g, 0.0055moles). 2-bromo-3-bromomethylthiophene (0.44 g, 0.0017 moles) was addedin one portion and the mixture stirred for 16 hours. The reactionmixture was filtered and evaporated in vacuo. The residue was extractedinto ethyl acetate and then washed with water and brine. After dryingover MgSO₄ and evaporation in vacuo the residue was purified bychromatography eluting with 20% ethyl acetate in methylene chloride. Therequired product was dissolved in ether and treated with ethereal HCl toafford a white solid upon removal of solvents in vacuo.

Anal. Calcd. for C₂₉ H₃₄ N₄ O₄ SBrCl.HCl.1.56H₂ O: C, 51.32; H, 5.52; N,8.26.

Found: C, 51.32; H, 5.48; N, 8.15.

MS (CI) 613/615 (M+1).

EXAMPLE 82 MethylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(4thiazolylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(4thiazolylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.750 g, 1.7 mmol) in DMF (20 mL) was added sodium hydride (60%) (0.17g, 0.0043 moles). 4-chloromethylthiazole.hydrochloride (0.22 g, 0.0013moles) was added in one portion and the mixture stirred for 64 hours.The reaction mixture was filtered and evaporated in vacuo. The residuewas extracted into ethyl acetate and then washed with water and brine.After drying over MgSO₄ and evaporation in vacuo the residue waspurified by chromatography eluting with 20% ethyl acetate in methylenechloride. The required product was dissolved in ether and treated withethereal HCl to afford a white solid upon removal of solvents in vacuo.

Anal. Calcd. for C₂₉ H₃₄ N₄ O₄ SBrCl.HCl: C, 58.62; H, 6.16; N, 12.22.

Found: C, 57.84; H, 6.09; N, 11.84.

MS (CI) 536 (M+1).

EXAMPLE 83 MethylZ-1-[4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]phenyl]cyclopentanecarboxylate

MethylZ-1-[4-[(2-butyl-5-formyl-1H-imidazol-1-yl]methyl]phenyl]cyclopentanecarboxylatewas added to a solution of 3-butyl-2,5-dioxo-4-imidazolylphosphonate(2.42 g, 9.00 mmol) and DBU (1.31 g, 8.6 mmol) in methylene chloride (10mL). This mixture was allowed to stand for 16 h at room temperature.This mixture was then purified by chromatography, eluant (1-10)%methanol in choroform, and recrystallisation from hot ethyl acetate andether. 1H-NMR indicated a small amount of the E-isomer was present inthe purified Z-isomer fraction.

Anal. Calcd. for C₂₉ H₃₈ N₄ O₄ : C, 68.75; H, 7.56; N, 11.06.

Found: C, 68.63; H, 7.55; N, 10.98.

MS (CI) 507 (M+1).

EXAMPLE 84Methyl-Z-1-[4-[[2-butyl-5-[[1-butyl-[3-(2-methyl-4-thiazoly)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]phenyl]cyclopentanecarboxylatemonohydrochloride

MethylZ-1-[4-[[2-butyl-5-[[1-butyl-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]phenyl]cyclopentanecarboxylate (1.00 g, 1.97 mmol) and4-chloromethyl-2-methylthiazole monohydrochloride (0.363 g, 1.97 mmol)was dissolved in DMF (10 mL). K₂ CO₃ (3.0 g, 21.7 mmol) was added andthe mixture stirred for 16 hours. The mixture was filtered andevaporated. The residue was added to water and the gum that formed wasdissolved in ether. After washing the ethereal fraction with water anddrying over K₂ CO₃ the product was purified by chromatography, eluant(0.5--3)% methanol in chloroform. The appropriate fraction was dissolvedin ether and treated with ethereal HCl. The solid foam that resultedupon extended evaporation in vacuo was collected and shown by 1H NMR tocontain the required product as well as the corresponding E-isomer(10%).

Anal. Calcd. for C₃₄ H₄₃ N₅ O₄ S.HCl.H₂ O: C, 60.74; H, 6.90; N, 10.42.

Found: C, 61.09; H, 6.78; N, 10.48.

MS (CI) 618 (M+1).

EXAMPLE 85Z-1-[4-[[2-butyl-5-[[1-butyl-[3-(2-methyl-4-thiazoly)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]phenyl]cyclopentanecarboxylicacid

MethylZ-1-[4-[[2-butyl-5-[[1-butyl-2,5-dioxo-[3-(2-methyl-4-thiazoly)methyl]-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]phenyl]cyclopentanecarboxylicmonohydrochloride (0.340 g, 0.5 mmol) and 2N HCl (15 mL) were heated atreflux for 2 hours. After evaporation in vacuo the residue was dissolvedin methanol and treated with saturated aqueous NaOAc to precipitate agum. This gum crystallized from ethyl acetate and was thenrecrystallized from methanol.

Anal. Calcd. for C₃₃ H₄₁ N₅ O₄ S: C, 65.65; H, 6.84; N, 11.60.

Found: C, 65.43; H, 6.74; N, 11.22.

MS (CI) 604 (M+1).

EXAMPLE 86 MethylE-4-[[2-butyl-5-[[3-butyl-1-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatedihydrochloride

To a solution of methylE-4-[[2-butyl-5-[[3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate(0.66 g, 1.5 mmol) in DMF (10 mL) is added K₂ CO₃ (3.0 g, 15 mmol).After stirring for 5 minutes 2-methyl-4-chloromethylthiazolehydrochloride (0.28 g, 1.5 mmol) is added. The mixture is stirred for 16hours and then filtered. The filtrate is concentrated in vacuo anddissolved in ether (50 mL). This solution is washed with water and driedover K₂ CO₃ and charcoal. The mixture is filtered and allowed to standin which time the product crystallizes. Petroleum ether is added tocomplete crystallization.

Anal. Calcd. for C₂₉ H₃₅ N₅ O₄ S: C, 63.37; H, 6.42; N, 12.74.

Found: C, 63.46; H, 6.38; N, 12.72.

mp 109°-111° C.; MS (CI) 550 (M+1).

EXAMPLES 87a AND 87b 87a MethylZ-4-[[2-butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoate

To a solution of diethyl 3-butyl-2,5-dioxo-4-imidazolylphosphonate (0.49g, 1.72 mmol) in acetonitrile (5 mL) was added lithium chloride (0.15 g,3.47 mmol) and then DBU (0.52 mL, 3.47 mmol). This mixture was stirredfor 5 minutes under N₂. Methyl4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]-3-chlorobenzoate (0.48 g,1.43 mmol) in acetonitrile (5 mL) was added and the mixture stirred for4 days. The solvent was removed in vacuo and the isomers separated bychromatography eluting with (1-5)% methanol in chloroform.

Anal. Calcd. for C₂₄ H₂₉ N₄ O₄ Cl: C, 60.95; H, 6.18; N, 11.85.

Found: C, 60.50; H, 6.11; N 11.30.

MS (CI) 473 (M+1).

87b MethylE-4-[[2-butyl-5-[[3-butyl-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoate

Anal. Calcd. for C₂₄ H₂₉ N₄ O₄ Cl: C, 60.95; H, 6.18; N, 11.85.

Found: C, 60.47; H, 6.06; N, 11.23.

mp 186°-187° C.; MS (CI) 473 (M+1).

EXAMPLES 88a AND 88b 88a MethylZ-1-[4-[[2-butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]phenyl]cyclohexanecarboxylate

MethylZ-1-[4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]phenyl]cyclohexanecarboxylatewas added to a solution of 3-butyl-2,5-dioxo-4-imidazolylphosphonate(0.16 g, 0.58 mmol) and sodium hydride (80% in oil) (0.032 g, 1.16 mmol)in methanol (3 mL). This mixture was allowed to stir for 16 hours atroom temperature. This mixture was then purified by chromatography,eluant (1-10)% methanol in chloroform. The Z-isomer was separated fromthe E-isomer.

Anal. Calcd. for C₃₀ H₄₀ N₄ O₄ : C, 69.20; H, 7.74; N, 10.75.

Found: C, 68.85; H, 7.67; N, 10.46.

mp 139°-140° C.; MS (CI) 521 (M+1).

88b MethylE-1-[4-[[2-butyl-5-[[3-butyl-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]phenyl]cyclohexanecarboxylate

Anal. Calcd. for C₃₀ H₄₀ N₄ O₄ : C, 69.20; H, 7.74; N, 10.76.

Found: C, 68.90; H, 7.80; N, 10.55.

mp 189°-190° C.; MS (CI) 521 (M+1).

EXAMPLE 89 MethylZ-4-[[2-butyl-5-[[1-(cyclopropylmethyl)-2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-cyclopropylmethyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate(0.39 g, 0.89 mmol) in DMF (5 mL) is added K₂ CO₃ (0.67 g, 4.47 mmol).After stirring for 5 minutes 3-bromomethylthiophene (1.20 mmol) isadded. The mixture is stirred for 16 hours. The mixture is diluted withethyl acetate and washed with water and dried over MgSO₄. Afterpurification by chromatography, eluting with (0-40)% ethyl acetate inmethylene chloride, the hydrochloride is prepared by the addition ofethereal HCl. The product is crystallized from ethyl acetate.

Anal. Calcd. for C₂₉ H₃₂ N₄ O₄ S: C, 61.20; H, 5.84; N, 9.84.

Found: C, 61.07; H, 5.82; N, 9.50.

mp 184°-190° C.; MS (CI) 533 (M+1).

EXAMPLE 90 MethylE-4-[[5-[(3-butyl-1-methyl-2,5-dioxo-4-imidazolidinylidene)methyl]-2-propyl-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylE-4-[[5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-2-propyl-1H-imidazol-1-yl]methyl]benzoate(0.082 g, 0.07 mmol) in DMF (0.5 mL) is added K₂ CO₃ (0.50 g, 3.62 mmol)and then methyliodide (0.24 g, 0.17 mmol). After stirring for 1 hour afurther amount of 1-iodomethane is added (0.024 g, 0.17 mmol). Themixture is stirred for an additional 1 hour. The mixture is diluted withwater and the gum that precipitates is collected by decantation. Thisgum is dissolved in methylene chloride and treated with charcoal and K₂CO₃. This mixture is filtered, concentrated and crystallized from ether.

Anal. Calcd. for C₂₄ H₃₀ N₄ O₄ 0.3 H₂ O: C, 65.20; H, 6.93; N, 12.67.

Found: C, 65.16; H, 6.88; N, 12.60.

mp 13°-114° C.; MS (CI) 439 (M+1).

EXAMPLE 91Z-1-Butyl-5-[[2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]-2,4-imidazolidinedione

To Z-1-butyl-5-[[2-butyl-3-[[2'-(N-triphenylmethyl-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]-2,4-imidazolidinedione(0.800 g, 1.04 mmol) was added methanol (100 mL) and 5% aqueous citricacid (5 mL). This white heterogenous mixture was refluxed for 3 hour inwhich time a solution formed. The solution was cooled to roomtemperature and diluted with water (10 mL) and hexanes (100 mL). Theaquous methanol fraction was evaporated in vacuo and then dissolved in amixture of ethyl acetate and water. After drying the organic fractionover Na₂ SO₄ the product was precipitated by the addition of ether to amethylene chloride solution.

HPLC eluant 55% (0.1%TFA in H₂ O) 45% MeCN, RT 2.98 [99%].

MS (CI) 525 (M+1).

EXAMPLE 92E-1-Butyl-5-[[2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4yl]methylene]-2,4-imidazolidinedione

ToE-1-butyl-5-[[2-butyl-3-[[2'-(N-triphenylmethyl-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]-2,4-imidazolidinedione(0.100 g, 0.13 mmol) was added methanol (50 mL) and 5% aqueous citricacid (5 mL). This white heterogenous mixture was refluxed for 3 hour inwhich time a solution formed. The solution was cooled to roomtemperature and diluted with water (10 mL) and hexanes (100 mL). Theaquous methanol fraction was evaporated in vacuo and then dissolved in amixture of ethyl acetate and water. After drying the organic fractionover Na₂ SO₄ the solvents were removed in vacuo and the residuetriturated with hexanes.

HPLC eluant 45%(0.1%TFA in H₂ O) 55% MeCN, RT 2.25 [95%].

MS (CI) 525 (M+1).

EXAMPLE 93Z-5-[[2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]1-methyl-2,4-imidazolidinedione

ToZ-5-[[2-butyl-3-[[2'-(N-triphenylmethyltetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]-1-methyl-2,4-imidazolidinedione(0.300 g, 0.414 mmol) was added methanol (50 mL) and glacial acetic acid(0.2 mL). This white heterogenous mixture was refluxed for 4 hours inwhich time a solution formed. The solution was cooled to roomtemperature and diluted with water (5 mL) and hexanes (50 mL). Theaquous methanol fraction was evaporated in vacuo and then dissolved in aminimal amount of methanol. Ether was added to precipitate a whitesolid.

Anal. Calcd. for C₂₆ H₂₆ N₈ O₂ 0.67H₂ O: C, 63.16; H, 5.57; N, 22.66.

Found: C, 63.43; H, 5.66; N, 22.33.

HPLC eluant 67% (0.1%TFA in H₂ O) 33% MeCN, RT 4.4 [92%].

MS (CI) 483 (M+1).

EXAMPLE 94E-5-[[2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]1-methyl-2,4-imidazolidinedione

To a mixture of the E and Z-isomers of5-[[2-butyl-3-[[2'-(N-triphenylmethyl-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methlylene-1-methyl-2,4imidazolidinedione(0.400 g, 0.552 mmol) was added methanol (50 mL) and glacial acetic acid(0.2 mL). This white heterogenous mixture was refluxed for 3 hour inwhich time a solution formed. The solution was cooled to roomtemperature an diluted with water (5 mL) and hexanes (50 mL). The aquousmethanol fraction was evaporated in vacuo and then triturated with ethylacetate. The insoluble residue was collected and determined to be theE-isomer.

HPLC eluant 45% (0.1%TFA in H₂ O) 55% MeCN, RT 1.9 [95%].

MS (CI) 483 (M+1).

EXAMPLE 951-Butyl-5-[[2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methyl]-2,4-imidazolidinedione

To a solution of1-butyl-5-[[2-butyl-3-[[2'-(N-triphenylmethyl-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methyl]-2,4-imidazolidinedione(0.080 g, 0.10 mmol) in methanol (30 mL) was added glacial acetic acid(0.06 mL). This mixture was refluxed for 5 hours. The solution wascooled to room temperature and diluted with water (10 mL) and hexanes(50 mL). The aquous methanol fraction was evaporated in vacuo and thenredissolved in a minimum volume of methanol. Ether was added and thesolid that precipitated collected.

HPLC eluant 67% (0.1%TFA in H₂ O) 33% MeCN, RT 5.4 [98%].

MS (CI) 527 (M+1).

Anal. Calcd. for C₂₉ H₃₄ N₈ O₂.H₂ O: C, 63.95; H, 6.66; N, 20.57.

Found: C, 64.15; H, 6.66; N, 20.07.

EXAMPLES 96a AND 96b 96a MethylZ-4'-[[2-butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl][1,1'-biphenyl]-2-carboxylate

To a solution of diethyl 3-butyl-2,5-dioxo-4-imidazolylphosphonate(0.540 g, 1.91 mmol) in methanol (15 mL) is added NaH (80% in oil, 0.115g, 3.83 mmol). The solution is stirrred for 5 minutes and then2-butyl-1-[(2'-carbomethoxy-1,1'-biphen-4-yl)methyl]-1H-imidazole-5-carboxaldehyde(0.515 g, 1.37 mmol) is added. The yellow solution is stirred for 16hours at room temperature and then diluted with ethyl acetate andsaturated ammonium chloride. The organic fraction is washed with brineand then dried over Na₂ SO₄.

Chromatography separates the Z and E-isomers, eluant (0.14 2)% methanolin chloroform.

Z-isomer

Anal. Calcd. for C₃₀ H₃₄ N₄ O₄ : C, 70.02; H, 6.66; N, 10.89.

Found: C, 69.58; H, 6.58; N, 10.55.

MS (CI) 515 (M+1).

96b Methyl E4'-[[2-butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl][1,1'-biphenyl]-2-carboxylate

Anal. Calcd. for C₃₀ H₃₄ N₄ O₄ : C, 70.02; H, 6.66; N, 10.89.

Found: C, 69.63; H, 6.54; N 10.65.

MS (CI) 515 (M+1).

EXAMPLE 97a AND 97b 97a MethylZ-4'-[[4-bromo-2-butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl][1,1'-biphenyl]-2-carboxylate

To a solution of diethyl 3-butyl-2,5-dioxo-4-imidazolylphosphonate(0.105 g, 0.372 mmol) in methanol (10 mL) is added sodium hydride (80%in oil, 0.022 g, 0.733 mmol). The solution is stirrred for 5 minutes andthen4-bromo-2-butyl-1-[(2'-carbomethoxy-1,1'-biphen-4-yl)methyl]-1H-imidazole-5-carboxaldehyde(0.130 g, 0.286 mmol) is added. The yellow solution is stirred for 16hours at room temperature and then diluted with ethyl acetate andsaturated ammonium chloride. The organic fraction is washed with brineand then dried over Na₂ SO₄. Chromatography separates the Z andE-isomers, eluant (30-50)% ethyl acetate in hexane.

Anal. Calcd. for C₃₀ H₃₃ N₄ O₄ Br: C, 60.71; H, 5.60; N, 9.44.

Found: C, 60.59; H, 5.71; N, 9.06.

MS (CI) 593/595.

97b MethylE-4'-[[4-bromo-2-butyl-5[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl][1,1'-biphenyl]-2-carboxylate

Anal. Calcd. for: C₃₀ H₃₃ N₄ O₄ Br: C, 60.71; H, 5.60; N, 944.

Found: C, 60.45; H, 5.48; N, 9.42.

MS (CI) 593/595.

EXAMPLE 98 MethylZ-4-[[2-butyl-5[2-[butyl[[(methoxymethyl)amino]carbonyl]amino]-2-carboxyethenyl]-1H-imidazol-yl]methyl]benzoate

To a solution of methylZ-4-[[2-butyl-5-[[3-butyl-1-(methoxymethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochlorde. (0.100 g, 0.193 mmol) in THF was added 1N NaOH (0.22mL, 0.22 mmol) and then methanol (2 mL). The yellow solution was stirredfor 1.5 hours and then 1N HCl (0.22 mL, 0.22 mmol) was added. Thereaction mixture was evaporated in vacuo to a white solid. This solidwas dissolved in ethyl acetate and water. The organic layer was driedbriefly over MgSO₄ and then concentrated to 1/6 original volume. Anequal volume of hexane was added and the solid collected.

Anal. Calcd. for: C₂₆ H₃₆ N₄ O₆ : C, 62.38; H, 7.25; N, 11.19.

Found: C, 61.97; N, 7.17; N, 11.15.

mp 155° C.; MS (FAB) 501.

EXAMPLE 99Z-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-[1-(phenylmethyl)-1H-imidazol-2-yl]methyl-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate hydrochloride (0.190 g, 0.400mmol) After stirring for 5 minutes1-(phenylmethyl)-2-chloromethyl-1H-imidazole monohydrochloride (0.130 g,0.53 mmol) is added. The mixture is stirred for 16 hours to generate abrown colored mixture. After diluting with ethyl acetate and washingwith water and brine the solution is dried over MgSO₄. A viscous oil isobtained upon chromatography on silica gel (eluant 0.5% methanol inchloroform) and evaporation of the solvents in vacuo. This oil isdissolved in ether and treated with ethereal HCl to afford a foamy solidupon evaporation in vacuo. This solid is crystallized from2-propanol/methanol/ether.

Anal. Calcd. for C₃₅ H₄₀ N₆ O₄. 2HCl. 0.67H2O: C, 61.67; H, 6.21; N,12.33.

Found: C, 61.06; H, 6.14; N, 11.98.

mp 247°-248° C.; MS (EI) 608.

EXAMPLE 100 MethylZ-4-[[2-butyl-5-[[2,5-dioxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate

To a solution of methylZ-4-[[2-butyl-5-[(2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate(0.200 g, 0.524 mmol) in DMF (2 mL) is added sodium hydride (80% in oil,0.02 g, 0.67 mmol) and the mixture stirred for 5 minutes.(Trimethylsilyl)ethoxymethyl chloride SEM-Cl (0.100 mL, 0.536 mmol) isadded and the mixture allowed to stir for 16 hours. The solvents areremoved in vacuo and the residue dissolved in ethyl acetate and water.After drying thr organic fraction over MgSO₄ the required product isisolated by chromatography, eluting with 0.5% methanol in chloroform.Crystallized from ether.

Anal. Calcd. for C₂₆ H₃₆ N₄ O₅ Si: C, 60.90; H, 7.08; N, 10.93.

Found: C, 60.81; H, 7.09; N, 10.73.

mp 146°-148° C.; MS (CI) 513.

EXAMPLE 101 MethylZ-4-[[2-butyl-5-[[1-(hydroxymethyl)-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatedihydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[2,5-dioxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.390 g, 0.760 mmol) in DMF (5 mL) is added K₂ CO₃ (0.525 g, 3.80mmol). After stirring for 5 minutes 4-chloromethyl-2-methylthiazolehydrochloride (0.275 g, 1.49 mmol) is added. The mixture is stirred for16 hours. Water is added and the gum that precipitates is separated.This gum is dissolved in ethyl acetate, washed with water and brine, andthen dried over MgSO₄. Chromatography eluting with 0.5% methanol inchloroform and evaporation in vacuo affords a viscous oil. This oil isdissolved in methylene chloride (5 mL) and treated with trifluoroaceticacid (5 mL). After stirring for 90 minutes the mixture is concentratedin vacuo and then extracted into methylene chloride from pH 7 buffer.The organic phase is dried over MgSO₄₄ and then evaporated in vacuo toafford an oil. This oil is disssolved in 2-propanol and treated withethereal HCl (1M, 2 mL). The white gummy solid that results iscrystallized from methanol/2-propanol/ether.

Anal. Calcd. for C₂₆ H₂₉ N₅ O₅ S. 2HCl: C, 52.35; H, 5.24; N, 11.74.

Found: C, 52.25; H, 5.32; N, 11.55.

mp 208°-211° C.; MS (CI) 522.

EXAMPLE 102 MethylZ-4-[[5-[[3-[(1,1'-biphenyl)-4-ylmethyl]-1-butyl-2,5-dioxo-4-imidazolidinylidene]methyl]-2-butyl-1-H-imidazol-1-yl]methyl]benzoate

To a solution of methylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.438 g, 1.00 mmol) in DMF (10 mL) is added K₂ CO₃ (0.42 g, 3.00 mmol).After stirring for 5 minutes biphenylmethyl chloride (0.210 g, 1.00mmol) is added. The mixture is stirred for 16 hours, filtered, andevaporated in vacuo. The gum is dissolved in ethyl acetate and washedwith water, brine and dried over MgSO₄. Chromatography eluting with(50-100)% ethyl acetate in hexane, evaporation in vacuo affords a foam.

Anal. Calcd. for C₃₇ H₄₀ N₄ O₄. 0.3H₂ O: C, 72.84; H, 6.71; N, 9.18.

Found: C, 72.73; H, 6.75; N, 9.12.

MS (CI) 604.

EXAMPLE 103 MethylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-[2-oxo-2-(2-thienyl)ethyl]-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate(0.660 g, 1.50 mmol) in DMF (10 mL) is added sodium hydride (60% in oil,0.08 g, 2.0 mmol). After stirring for 5 minutes 2-(bromoacetyl)thiophene(0.500 g, 2.44 mmol) is added. The mixture is stirred for 16 hours,filtered and evaporated in vacuo. The gum is dissolved in ethyl acetateand washed with water, brine and dried over MgSO₄. Chromatographyeluting with (0-5)% methanol in dichloromethane and evaporation in vacuoaffords a foam. The hydrochloride salt is prepared.

Anal. Calcd. for C₃₀ H₃₄ N₄ O₄ S. HCl. H₂ O: C, 58.38; H, 6.04; N, 9.08.

Found: C, 58.21; H, 5.99; N, 8.74.

MS (CI) 563.

EXAMPLE 104 MethylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(2-oxo-2-phenylethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.660 g, 1.50 mmol) in DMF (10 mL) is added K₂ CO₃ (0.62 g, 4.5 mmol).After stirring for 5 minutes (bromoacetyl)benzene (0.320 g, 1.6 mmol) isadded. The mixture is stirred for 16 hours, filtered, and evaporated invacuo. The gum is dissolved in ethyl acetate and washed with water,brine and dried over MgSO₄. Chromatography eluting with (50-100)% ethylacetate in hexane and evaporation in vacuo affords a foam. Thehydrochloride salt is prepared.

Anal. Calcd. for C₃₂ H₆ N₄ O₅ S. HCl. H₂ O: C, 62.89; H, 6.43; N, 9.17.

Found: C, 62.74; H, 6.43; N, 9.03.

MS (CI) 557.

EXAMPLE 105Z-4-[[2-Butyl-5-[[2,5-dioxo-1,3-bis(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid

To a solution of 1,1-dimethylethylZ-4-[[2-butyl-5-[(2,5-dioxo-4-imidazolidinylidene)methyl]benzoate (0.660g, 1.55 mmol) in DMF (5 mL) and THF (5 mL) is added NaH (0.13 g, 3.25mmol). After stirring for 5 minutes 2-thienylmethyl bromide (0.58 g,3.28 mmol) is added. The mixture is stirred for 16 hours, filtered andevaporated in vacuo. The gum is dissolved in ethyl acetate and washedwith water, brine and dried over MgSO₄. Chromatography eluting with(50-100)% ethyl acetate in hexane and evaporation in vacuo affords afoam. This foam is dissolved in methylene chloride (15 mL) andtrifluoroacetic acid (4 mL) is added. The mixture is evaporated in vacuoand then dissolved in ethyl acetate. After washing with pH 4 buffer anddrying over MgSO₄₄ the product is isolated by chromatography, eluant(2-5)% methanol in chloroform. Crystallized from THF/Ether

Anal. Calcd. for C₂₉ H₂₈ N₄ O₄ S₂.H₂ O: C, 62.12; H, 5.03; N, 9.99.

Found: C, 62.24; H, 5.05; N, 9.90.

mp 204°-205° C.; MS (CI) 561.

EXAMPLE 106 MethylZ-4-[[2-butyl-5-[[1-butyl-3-(5-isoxazolyl-methyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-Butyl-5-[[1-butyl-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.420 g, 0.96 mmol) in DMF (20 mL) is added K₂ CO₃ (0.40 g, 4.5 mmol).After stirring for 5 minutes 5-bromomethylisoxazole (0.160 g, 1.00 mmol)is added. The mixture is stirred for 16 hours, filtered and evaporatedin vacuo. The gum is dissolved in ethyl acetate and washed with waterand, brine, and dried over MgSO₄. Chromatography eluting with (0-5)%methanol in methylene chloride and evaporation in vacuo affords a foam.The hydrochloride salt was prepared.

Anal. Calcd. for C₂₈ H₃₃ N₅ O₅. HCl. 1.6 H₂ O: C, 57.50; H, 6.41; N,11.97.

Found: C, 57.19; H, 6.41; N, 11.70.

MS (CI) 520.

EXAMPLE 107 MethylZ-4-[[2-butyl-5-[[2,5-dioxo-4,4,4-(trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate

To a solution of diethyl2,5-dioxo-1-[4,4,4-(trifluorobutyl)]-4-imidazolylphosphonate (2.43 g,7.01 mmol) in methylene chloride (15 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.07 g, 7.02 mmol). The yellow solution is stirredfor 10 minutes and then a solution of methyl4[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoate (2.11 g, 7.01 mmol)was added. This mixture is allowed to stir for 16 hours. The mixture isdiluted with ethyl acetate and washed with water and then brine. Afterdrying over MgSO₄ the product is isolated as a yellow solid byconcentration in vacuo and treatment with ether. Crystallized from ethylacetate.

Anal. Calcd. for C₂₄ H₂₇ N₄ O₄ F₃ : C, 58.53; H, 5.53; N, 11.38.

Found: C, 58.93; H, 5.51; N, 11.28.

mp 188°-189° C.; MS (CI) 493.

EXAMPLE 108 MethylZ-4-[[2-butyl-5-[[1-butyl-3-[(5-methyl-3-isoxazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate

To a solution of methylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(0.700 g, 1.60 mmol) in DMF (14 mL) is added K₂ CO₃ (1.10 g, 7.98 mmol).After stirring for 5 minutes 3-chloromethy-5-methyllisoxazole [approx.90% pure] (0.42 g, 1.00 mmol) is added. The mixture is stirred for 16hours, filtered, and evaporate din vacuo. The gum is dissolved in ethylacetate and washed with water, brine and dried over MgSO₄.Chromatography eluting with (2-5)% methanol in methylene chloride andevaporation in vacuo affords a solid gum.

Anal. Calcd. for C₂₉ H₃₅ N₅ O₅ : C, 65.27; H, 6.61; N, 13.12.

Found: C, 65.31; H, 6.66; N, 12.81.

MS (CI) 534.

EXAMPLE 109 MethylZ-4-[[2-butyl-5-[[1-ethyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatedihydrochloride

To a solution of MethylZ-4-[[2-Butyl-5-[[1-ethyl-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate(1.28 g, 3.23 mmol) in DMF (15 mL) is added K₂ CO₃ (2.68 g, 19.42 mmol).After stirring for 5 minutes 4-chloromethyl-2-methylthiazolehydrochloride (0.624 g, 3.39 mmol) is added. The mixture is stirred for3 days. A further amount of 4-chloromethyl-2-methylthiazolehydrochloride (1.248 g, 6.78 mmol) was added as well as an additionalamount of K₂ CO₃ (1.34 g, 9.7 mmol). The thick mixture was stirred for 2days. The mixture was filtered and evaporated in vacuo. The gum wasdissolved in ethyl acetate and washed with water, brine and dried overMgSO₄. Chromatography eluting with (40-100)% ethyl acetate in hexane.The hydrochloride salt was prepared by the addition of ethereal HCl tothe product in ethyl acetate. The salt was recrystallized fromi-propanol/ether.

Anal. Calcd. for C₂₇ H₃₁ N₅ O₄ S.2HCl: C, 54.54; H, 4.49; N. 11.78.

Found: C, 54.18; H, 5.54; N, 11.45.

MS (CI) 552.

EXAMPLE 110 MethylZ-4-[[2-butyl-5-[[1-butyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoate monohydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoate (0.700 g, 1.48 mmol) in DMF (10 mL) is added K₂ CO₃ (1.02 g,7.40 mmol). After stirring for 5 minutes 4-chloromethyl-2-methylthiazolehydrochloride (0.54 g, 2.96 mmol) is added. The mixture is stirred for16 hours. The mixture was filtered and evaporated in vacuo. The gum wasdissolved in ethyl acetate and washed with water, brine and dried overMgSO₄. Chromatography eluting with 50% ethyl acetate in methylenechloride. The hydrochloride salt was prepared by the addition of etheralHCl to the product in ether. The salt was recrystallized fromi-propanol/ether.

Anal. Calcd. for C₂₉ H₃₄ N₅ O₄ SCl 1.13 HCl 1.26 H₂ O: C, 53.95; H,5.86; N, 10.84.

Found: C, 53.75; H, 5.67; N, 10.45.

MS (CI) 584.

EXAMPLE 111 Methyl Z-4-[[2-Butyl-5-[[3-[2-methyl-4-thiazoly)methyl]-2,5-dioxo-1-(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatedihydrochloride

To a solution of methylZ-4-[[2-butyl-5-[[2,5-dioxo-1-(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate.(1.00 g, 2.03 mmol) in DMF (15 mL) is added K₂ CO₃ (1.92 g, 14.20 mmol).After stirring for 5 minutes 4-chloromethyl-2-methylthiazolehydrochloride (0.56 g, 3.05 mmol) is added. The mixture is stirred for18 hours. The mixture was filtered and evaporated in vacuo. The gum wasdissolved in ethyl acetate and washed with water and then brine. Driedover MgSO₄. The hydrochloride salt was prepared by the addition ofethereal HCl to the product in ether. The salt was recrystallized fromi-propanol/ether.

Anal. Calcd. for C₂₉ H₃₃ N₅ O₄ SF₃ 2HCl 1.5 H₂ O: C, 49.50; H, 5.30; N,9.95.

Found: C, 49.90; H, 5.31; N, 9.89

MS (CI) 604; mp 132°-134° C.

EXAMPLE 112 MethylZ-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatedihydrochloride

To a solution of methylZ-4-[[2-butyl-5-[1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate.(0.70 g, 1.59 mmol) in DMF (15 mL) is added K₂ CO₃ (1.10 g, 7.98 mmol).After stirring for 5 minutes 4,4,4-trifluoromethyl-1-iodobutane (0.38 g,1.59 mmol) is added and the mixture stirred for 18 hours. The mixturewas filtered and evaporated in vacuo. The gum was dissolved in ethylacetate and washed with water, brine and dried over MgSO₄. Thehydrochloride salt was prepared by the addition of ethereal HCl to theproduct in ether. The salt was recrystallized from i-propanol/ether.

Anal. Calcd. for C₂₈ H₃₅ N₄ O₄ F₃. 1HCl: C, 57.40; H, 6.20; N, 9.58.

Found: C, 57.38; H, 6.11; N, 9.44.

MS (CI) 549; mp 161°-162° C.

EXAMPLE 113 MethylZ-4-[[2-butyl-5-[[2,5-dioxo-1,3-bis(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of methylZ-4-[[2-Butyl-5-[1-(4,4,4-trifluorobutyl)-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate.(0.98 g, 2.80 mmol) in DMF (10 mL) is added K₂ CO₃ (1.95 g, 14.15 mmol).After stirring for 5 minutes 4,4,4-trifluoromethyl-1-iodobutane (0.74 g,3.10 mmol) is added and the mixture stirred for 18 hours. The mixturewas filtered and evaporated in vacuo. The gum was dissolved in ethylacetate and washed with water, brine and dried over MgSO₄. Thehydrochloride salt was prepared by the addition of ethereal HCl to theproduct in ether. The salt was recrystallized from i-propanol/ether.

Anal. Calcd. for C₂₈ H₃₂ N₄ O₄ F₆. 1HCl: C, 52,63; H, 5.21; N, 8.77.

Found: C, 52.78; H, 5.18; N, 8.62.

MS (CI) 603; mp 141°-142° C.

EXAMPLE 114Z-1-Butyl-5-[[2-butyl-3-(triphenylmethyl)-3H-imidazol-5-yl]methylene]-2,4-imidazolidinedione

To a solution of diethyl 1-butyl-2,5-dioxo-4-imidazolidinylphosphonate(2.94 g, 10 mmol) in methylene chloride (10 mL) was added DBU (1.5 mL,10 mmol) and the mixture stirred for 5 minutes.2-butyl-1-(triphenylmethyl)-1H-imidazol-4-carboxaldehyde (2.20 g, 5.58mmol) was added and the yellow solution stirred for 16 hours. Themixture was evaporated in vacuo, redissolved in ethyl acetate, andwashed with water and then brine. After drying over MgSO₄ the productwas isolated by chromatography on silica eluting with chloroform.

MS (CI) 533.

EXAMPLE 115Z-1,3-Dibutyl-5-[[2-butyl-3-(triphenylmethyl)-3H-imidazol-5-yl]methylene]-2,4-imidazolidinedione

To a solution ofZ-1-butyl-5-[[2-butyl-3-(triphenylmethyl)-3H-imidazol-5-yl]methylene]-2,4-imidazolidinedione(1.20 g, 2.26 mmol) in DMF (5 mL) was added K₂ CO₃ (1.56 g, 11.3 mmol)and then 1-iodobutane (0.344 mL, 3.02 mmol). The mixture was stirred for16 hours and then diluted with ether and washed with water and brine.After drying over MgSO₄ the product was isolated by chromatography onsilica eluting with 80% petroleum ether 20% ethyl acetate.

MS (CI) 588.

EXAMPLE 116 MethylZ-4-[[2-butyl-5-[(1,3-dibutyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoatemonohydrochloride

To a solution of trifluoromethanesulfonic anhydride (0.094 mL, 0.56mmol) in methylene chloride (10 mL) at -78° C. was added a solution ofmethyl 4-(hydroxymethyl)benzoate (0.093 g, 0.56 mmol) andN,N-diisopropylethylamine (0.098 mL, 0.56 mmol) in methylene chloride(10 mL) dropwise over 5 minutes. This solution was stirred for 15minutes and then a solution ofZ-1,3-dibutyl-5-[[2-butyl-3-(triphenylmethyl)-3H-imidazol-5-yl]methylene]-2,4-imidazolidinedione(0.330 g, 0.56 mmol) in methylene chloride (5 mL) was added dropwise.The mixture was allowed to slowly warm to room temperature within thecooling bath overnight. Glacial acetic acid (10 mL) and water (2 mL)were added and the mixture boiled for 1 hour on a steam bath. Afterevaporation in vacuo the residue was dissolved in ethyl acetate, washedwith saturated NaHCO₃ and brine, and then dried over MgSO₄.Chromatography eluting with CHCl₃ afforded the required product withspectral characteristics identical with the produce formed in Example33.

We claim:
 1. A compound of formula ##STR18## or a pharmaceutically saltthereof wherein: R₁ ishydrogen, straight or branched alkyl or alkenylfrom 1 to 8 carbon atoms; alkyl as above substituted with HO, NO₂, CN,NH₂, CO₂ CH₃, CO₂ C₂ H₅, or CONH₂ ; (CH₂)_(n) aryl wherein n is aninteger from 0 to 4 and aryl is Ph or Ph substituted with Cl, Br, I, F,CH₃, OCH₃, OH, NO₂, CF₃, CN, CONH₂, CO₂ H, NH₂, NHCH₃, or N(CH₃)₂groups, methylenedioxy; (CH₂)_(n) heteroaryl wherein n is an integerfrom 0 to 3 and heteroaryl is 2-thienyl, 3-thienyl, 2-furanyl,3-furanyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-thiazolyl, 2-oxazolyl, 2-imidazolyl, 4-thiazolyl, 4-oxazolyl,4-imidazolyl, 5-thiazolyl, 5-oxazolyl, 5-tetrazole, 3-isoxazole,4-isoxazole, or 5-isoxazole; (CH₂)_(n) heteroaryl as above substitutedwith Me, Et, Pr, Butyl, Cl, Br, I, F, OMe, OH, NO₂, NH₂, NHMe, NMe₂, CO₂R, CO₂ H, SO₂ NHR, SO₃ H, CONR₂, CN, CF₃. (CH₂)_(m) X(CH₂)_(n) H whereinX is O, S, or N and m and n are each independently integral from 1 to 6carbon atoms; (CH₂)_(n) cycloalkyl wherein n is an integer from 0 to 3and cycloalkyl is a saturated or unsaturated ring of 3 to 7 carbonatoms; R₂ iscycloalkyl of from 3 to 6 carbon atoms; alkyl of from 1 to 6carbon atoms, alkenyl of from 2 to 6 carbon atoms, OC₁ -C₅ alkyl, andSC₁ -C₅ alkyl; R₃ is(CH₂)_(n) CO₂ Y or ##STR19## wherein Y is hydrogenor lower alkyl, n is an integer of from 0 to 3, and m is an integer offrom 2 to 7; wherein R=C₁ -C₈ alkyl, CH₂ SO₂ NHCOR, NHSO₂ NHCOR,NHCONHSO₂ R, PO (OR)₂, CONHSO₂ R, SO₃ H, B(OH)₂, SO₂ NHCOR, ##STR20##SO₂ NHCONHR, NHSO₂ CF₃, ##STR21## R₄ =R₁ R₅ is hydrogen or alkyl of from1 to 4 carbon atoms; R₆ is hydrogen, chlorine, bromine, fluorine,methyl, trifluoromethyl, or methoxy; and R₇ is oxygen or sulfur.
 2. Acompound according to claim 1 wherein:R₁ ishydrogen, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-amyl,i-amyl, n-hexyl, aryl, CH₂ -aryl, CH₂ -heteroaryl, with H, Me, Cl, OMe,NH₂, NMe₂, substituents, or CH₂ -cycloalkyl wherein aryl, heteroaryl,and cycloalkyl are as defined in claim 1; R₂ ispropyl, i-propyl,n-butyl, n-pentyl, or cyclopropylmethyl, R₃ is(CH₂)_(n) CO₂ Y or##STR22## wherein Y is hydrogen or lower alkyl, n is 0 or 1, m is 2 to5; R₄ is hydrogen, alkyl or branched alkyl of from 1 to 8 carbon atoms,(CH₂)_(m) X(CH₂)_(n) H m=1-6, n=1-6, and X=O, N, S; R₅ is hydrogen; R₆ishydrogen, chlorine, fluorine, methyl, trifluoromethyl, or methoxy; andR₇ is oxygen.
 3. A compound according to claim 1 wherein:R₁ is n-butyl,n-pentyl, n-propyl, benzyl, 2-thienylmethyl, 3-thienylmethyl,cyclopropylmethyl, cyclohexylmethyl, cyclopentylmethyl,2-methyl-4-thiazolylmethyl, 2-amino-4-thiazolylmethyl, or4-thiazolylmethyl, 2-amino-4-thienylmethyl, 2-methyl-4-thienylmethyl; R₂is butyl and propyl; R₃ is(CH₂)_(n) CO₂ Y wherein n is O, Y is hydrogenor methyl; R₄ is hydrogen or alkyl of 3 to 6 carbons; R₅ and R₆ are eachhydrogen; and R₇ is oxygen.
 4. A compound according to claim 1 selectedfrom:(E)-4-[[2-Butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid and its methyl ester,(Z)-4-[[2-Butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[2,5-dioxo-3-(3-methylbutyl)-4-imidazolidinylidene]methyl]-1H-imidazole-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[2,5-dioxo-3-(3-methylbutyl)-4-imidazolidinylidene]methyl]-1H-imidazole-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[(2,5-dioxo-3-methyl-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[(2,5-dioxo-3-methyl-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[(2,5-dioxo-3-(phenylmethyl)-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[(2,5-dioxo-3-(phenylmethyl)-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[(2,5-dioxo-3-phenyl-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[(2,5-dioxo-3-phenyl-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[2,5-dioxo-3-((2-thienyl)methyl)-4-imidazolidinylidene]-methyl]-1H-imidazole-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[2,5-dioxo-3-((2-thienyl)methyl)-4-imidazolidinylidene]methyl]-1H-imidazole-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[2,5-dioxo-3-(4-hydroxybutyl)-4-imidazolidinylidene]methyl]-1H-imidazole-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[2,5-dioxo-3-(4-hydroxybutyl)-4-imidazolidinylidene]methyl]-1H-imidazole-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Propyl-5-[(3-butyl-1-methyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Propyl-5-[(3-butyl-1-methyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazole-1-yl]methyl]benzoicacid or its methyl ester.(Z)-4-[[2-Butyl-5-[[3-[(4-chlorophenyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[3-[(4-chlorophenyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-butyl-3-(cyclohexylmethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-butyl-3-(cyclohexylmethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-butyl-2,5-dioxo-3-pentyl-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-butyl-2,5-dioxo-3-pentyl-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[(1,3-dibutyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[(1,3-dibutyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-butyl-2,5-dioxo-3-(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-butyl-2,5-dioxo-3-(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[2,5-dioxo-1,3-bis(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[2,5-dioxo-1,3-bis(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-butyl-2,5-dioxo-3-(3-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-butyl-2,5-dioxo-3-(3-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-butyl-2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-butyl-2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-butyl-3-[(5-methyl-2-thienyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-butyl-3-[(5-methyl-2-thienyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-butyl-2,5-dioxo-3-(4-thiazolylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-butyl-2,5-dioxo-3-(4-thiazolylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[3-[(2-methyl-4-thiazoly)methyl]-2,5-dioxo-1-(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[3-[(2-methyl-4-thiazoly)methyl]-2,5-dioxo-1-(4,4,4-trifluorobutyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-butyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-butyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-butyl-3-[(2-amino-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-butyl-3-[(2-amino-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-butyl-2,5-dioxo-3-(2-pyridinylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-butyl-2,5-dioxo-3-(2-pyridinylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methylbenzoic acid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-butyl-2,5-dioxo-3-(1H-tetrazol-5-ylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-butyl-2,5-dioxo-3-(1H-tetrazol-5-ylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-butyl-3-(1H-imidazol-5-ylmethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-butyl-3-(1H-imidazol-5-ylmethyl)-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-butyl-3-[(5-methyl-3-isoxazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-butyl-3-[(5-methyl-3-isoxazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-hexyl-2,5-dioxo-3-(3-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-hexyl-2,5-dioxo-3-(3-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[1-hexyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[1-hexyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-(cyclopropylmethyl)-2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-(cyclopropylmethyl)-2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-(methoxymethyl)-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-(methoxymethyl)-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-(hydroxymethyl)-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-(hydroxymethyl)-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[1-butyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoic acid or its methyl ester,(E)-4-[[2-Butyl-5-[[1-butyl-3-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoic acid or its methyl ester,(Z)-N-[4-[[2-Butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]phenyl]-1,1,1-trifluoromethanesulfonamide,(E)-N-[4-[[2-Butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]phenyl]-1,1,1-trifluoromethanesulfonamide,(Z)-1-Butyl-5-[[2-butyl-3-[[4-(1H-tetrazol-5-yl)phenyl]methyl]-3H-imidazol-4-yl]methylene]-2,4-imidazolidinedione,(E)-1-Butyl-5-[[2-butyl-3-[[4-(1H-tetrazol-5-yl)phenyl]methyl]-3H-imidazol-4-yl]methylene]-2,4-imidazolidinedione,(Z)-4-[[2-Butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoicacid and its methyl ester,(E)-4-[[2-Butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]-3-chlorobenzoicacid and its methyl ester,(Z)-1-Butyl-5-[[2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]-2,4-imidazolidinedione,(E)-1-Butyl-5-[[2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]-2,4-imidazolidinedione,1-Butyl-5-[[2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methyl]-2,4-imidazolidinedione,(Z)-5-[[2-Butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]1-methyl-2,4-imidazolidinedione,(E)-5-[[2-Butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]1-methyl-2,4-imidazolidinedione,(Z)-4'-[[2-Butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl][1,1'-biphenyl]-2-carboxylicacid or its methyl ester,(E)-4'-[[2-Butyl-5-[(3-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl][1,1'-biphenyl]-2-carboxylicacid or its methyl ester,(Z)-1-[4-[[2-Butyl-5-[[2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]phenyl]cyclopentanecarboxylicacid or its methyl ester,(E)-1-[4-[[2-Butyl-5-[[2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]phenyl]cyclopentanecarboxylicacid or its methyl ester,(Z)-1-[4-[[2-Butyl-5-[[1-butyl-[3-(2-methyl-4-thiazoly)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]phenyl]cyclopentanecarboxylicacid or its methyl ester,(E)-1-[4-[[2-Butyl-5-[[1-butyl-[3-(2-methyl-4-thiazoly)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]phenyl]cyclopentanecarboxylicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[2,5-dioxo-1,3-bis(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(E)-4-[[2-Butyl-5-[[2,5-dioxo-1,3-bis(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester,(Z)-4-[[2-Butyl-5-[[3-butyl-1-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester, and(E)-4-[[2-Butyl-5-[[3-butyl-1-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoicacid or its methyl ester.
 5. A pharmaceutical composition adapted foradministration as a hypertensive agent comprising a therapeuticallyeffective amount of a compound according to claim 1 in admixture with apharmaceutically acceptable excipient, diluent, or carrier.
 6. A methodof treating hypertension comprising administering to a host sufferingtherefrom a therapeutically effective amount of a compound according toclaim 1 in unit dosage form.